Introduction

Chronic obstructive pulmonary disease (COPD) has an increasing rate of incidence in recent years and causes three million deaths annually, which brings about a heavy economic burden.1 Currently, there are no effective target drugs applied to clinical practice so it is urgent to mine promising drug targets. Airway inflammation is an important feature and contributes to the pathogenesis and progression of COPD.2 Ferroptosis refers to the programmed cell death induced by lipid peroxidation via iron-dependent pathway with unique morphological and biological features.3 Usually under environmental stresses or intra/inter-cellular signaling, many metabolic products such as reactive oxygen species (ROS) and phospholipid containing polyunsaturated fatty acid chain(s) (PUFA-PL) can trigger phospholipid peroxidation.4 Previous study proved that ferroptosis was involved in the pathogenesis of COPD.5 Stimulated by cigarette smoke, bronchial epithelium produced reactive oxygen species, which induced lipid peroxidation, membrane damage and even ferroptosis.6–8 Glutathione peroxidase 4 (GPX4) – a vital antioxidant regulator – is also impaired during ferroptosis.9 Cigarette smoke extract altered ferroptosis-related genes expression in bronchoalveolar epithelial cells. Hypermethylation of the nuclear factor erythroid 2-related factor 2 (Nrf2) promoter could inhibit Nrf2/GPX4 axis, thus affecting ferroptosis in COPD.10 Otherwise, many studies suggest that various immune cells play vital roles in chronic airway diseases such as COPD. Innate immune cells, which were enhanced in small airways, modulated airway inflammation and remodeling.11 Previous study reported that CD8+ T cells enhanced ferroptosis-specific lipid peroxidation in tumor cells.12 The proliferation of B cells and antibody production was influenced by iron ion regulating the expression of Cyclin E1.13 Macrophages recognized oxidized phospholipids on the cell surface to clear ferroptosis cells via toll-like receptor 2 (TLR2).14 However, the interaction between ferroptosis and immune cells infiltration in COPD pathogenesis remains unclear.

The aim of this research is to identify ferroptosis-related hub genes and their association with immune cells infiltration in COPD lung tissues compared with normal ones. Additionally, we intend to construct interactive networks of hub genes with miRNAs, transcription factors and signal molecules and evaluate the diagnostic values of hub genes.

Materials and Methods

Data Acquisition

The mRNA expression microarray data of GSE38974,15 including 23 patients with COPD and 9 normal controls, were extracted from the Gene Expression Omnibus (GEO) datasets.16 The platform was GPL4133 Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version). Lung tissues from 9 smokers with no evidence of obstructive lung disease and 23 smokers with COPD were examined for mRNA expression. All the clinical information including age, gender, sample source, smoking history, GOLD stage and FVC group was publicly accessible in GEO database (www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE38974&platform=GPL4133).

The 259 ferroptosis-related genes (FRGs) were downloaded from the FerrDb database.17

Identification of Differentially Expressed FRGs

The GEO2R is a web tool internally stalled in GEO database specialized for analyzing differentially expressed genes between experimental group and control group. The GEO2R analysis between COPD group and control group was performed on the GEO datasets and the result of differential expression analysis was downloaded for further analysis. The cut‐off criteria for differential gene expression were the absolute value of log fold change (FC) >1 and P value <0.05. The gene list of differential expression analysis and FRGs were intersected to obtain the differentially expressed FRGs. The expressions of differentially expressed FRGs were plotted using the R package Complex Heatmap.18 The expression differences of differentially expressed FRGs between COPD group and normal group in GSE38974 were compared using Kruskal–Wallis test and Dunn’s test. The correlation analysis of differentially expressed FRGs was performed using Spearman’s correlation.

Gene Ontology (GO) Terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathways Analyses

The GO and KEGG enrichment analyses were conducted using the R package clusterProfiler.19 The screening criteria for significant terms were adjusted P values less than 0.05 and q values less than 0.2. Combined with logFC values, the enrichment analyses were performed by calculating the Z-scores using the R package GOplot.20

STRING Database and Cytoscape Software

The STRING database is an online tool for analyzing protein–protein interaction. The PPI analysis was carried out using the STRING database.21 Cytoscape is a computer software that graphically displays, analyzes and edits the network, which contains multiple plugins. The results were processed and visualized in Cytoscape software (version 3.9.0). The key module was screened by the Molecular Complex Detection (MCODE) plugin. The differentially expressed FRGs were ranked by degrees and the top five genes were considered to be hub genes by cytoHubba plugin.

The Comparative Toxicomics Database

The Comparative Toxicomics Database (CTD) provides integrated information on complex interactions among chemical exposures, genes, proteins and diseases.22 In this study, we used it to estimate the inference scores of hub genes in several respiratory tract diseases.

miRNet, NetworkAnalyst and Encyclopedia of RNA Interactomes (ENCORI)

There are multiple online tools to analyze the interaction between non-coding RNAs and genes and predict target molecules. The miRNet is a useful online tool centering around miRNAs and their interacting molecules.23 The NetworkAnalyst is an integrated and powerful database for gene expression analysis and construction of interacting networks.24 In this article, they were utilized to explore and visualize the networks between hub genes and miRNAs, transcription factors and signal molecules. The ENCORI focuses on predicting RNA interaction.25 Here, it was used to predict the upstream molecules lncRNAs targeting screened miRNAs. The screening criterion was set as strict stringency (the number of Ago CLIP-seq experiments is no less than five) and the top three lncRNAs were selected.

The Receiver Operating Characteristic (ROC) Curves of Hub Genes

The logistic regression model of hub genes was constructed using glm function in R software, and the ROC curves were plotted using R package pROC. The ROC curve of each hub gene can help us determine whether its expression has diagnostic value to some extent. The true positive rate (TPR) or sensitivity refers to the number of true positive samples detected divided by the number of all true positive samples. The false-positive rate (FPR) refers to the number of false-positive samples detected divided by the number of all true negative samples. Specificity refers to the number of true negative samples detected divided by the number of all true negative samples. The abscissa represents 1 – specificity and the ordinate represents sensitivity. The area under the curve (AUC) is used to determine the prediction accuracy. The AUC is usually between 0.5 and 1.0. The ROC curve has low/moderate/high accuracy when the AUC is 0.5~0.7/0.7~0.9/more than 0.9, respectively. The Youden’s index (sensitivity plus specificity minus one) is used to assess the authenticity of the model. As it gets closer to 1.0, the model is much more authentic.

CIBERSORT Algorithm

CIBERSORT is an R/web tool for deconvolution of expression matrices of human immune cell subtypes based on the principle of linear support vector regression.26 By the way of the CIBERSORT algorithm, we analyzed the proportions of 22 types of immune cells infiltration in patients with COPD and normal controls. The infiltration differences in patients with COPD and normal controls were compared using Kruskal–Wallis test and Dunn’s test. The Spearman correlation analysis was carried out to show the correlation within differentially infiltrated immune cells and the association between hub genes and differentially infiltrated immune cells.

Statistical Methods

All the statistical calculations were conducted in R software (version 3.6.3). The corresponding R packages were described as above. The statistical significance was marked as follows: ns, p≥0.05; *p< 0.05; **p < 0.01; ***p < 0.001. A p.adjust was the corrected p value obtained by the p value correction method; a q-value was an adjusted p-value, taking into account the false discovery rate (FDR). As the p value/p.adjust/q-value is less than 0.0001, scientific notation (exponent, E) is used. For instance, 0.0000267 is written as 2.67E-05.

Results

Identification of Differentially Expressed FRGs

The design of this research was shown in the flow chart (Figure 1). Principal component analysis (PCA) was conducted to show that there was a good degree of clustering between the two groups (Figure 2A). After intersection, 102 genes were obtained (Figure 2B). Under the condition of absolute values of logFC > 1 and P values <0.05, 15 differentially expressed FRGs were discovered including 11 upregulated genes and 4 downregulated genes (Table 1). The 15 differentially expressed FRGs between COPD and normal groups were presented in volcano plot and heatmap (Figure 2C and D). The volcano plot showed the distribution of gene expression between COPD and normal groups. Genes with an adjusted P-value <0.05 and absolute fold-change value > 1 were considered as differentially expressed genes. Each point represented one gene. Red dots indicated significantly upregulated genes and blue dots indicated significantly downregulated genes. The top three upregulated genes included IL6, ATM and TNFAIP3 and the top two downregulated genes included IL33 and TGFBR1. Furthermore, the expression differences of 15 differentially expressed FRGs between the COPD and normal groups in GSE38974 were shown in box plots (Figure 3A). As shown in Figure 3A, 15 ferroptosis-related genes were all significantly differentially expressed between COPD group and normal samples, which was consistent with Figure 2C and D. To explore the expression correlation of these ferroptosis-related genes, correlation analysis was performed. The Spearman correlation analyses of 15 differentially expressed FRGs were shown in heatmap (Figure 3B). As shown in Figure 3B, the expressions of most up-regulating genes were significantly positively correlated with each other, so were the down-regulating genes. Similarly, the expressions of the most up-regulated genes had a significantly negative correlation with those of the four down-regulated genes.

Table 1 The Differentially Expressed FRGs in COPD Group Compared with Normal Group

Figure 1 Flow chart.

Figure 2 Identification of differentially expressed ferroptosis-related genes (FRGs). (A) The principal component analysis (PCA) plot of samples in GSE38974. (B) Venn diagram of GEO2R result and FRGs. (C) Volcano plot of differential genes between COPD and normal groups. The top five genes were labelled (upregulated-IL6, ATM and TNFAIP3, downregulated-IL33 and TNFBR1). (D) Heatmap of 15 differentially expressed FRGs.

Figure 3 Expression and correlation of differentially expressed FRGs. (A) Box plot of 15 differentially expressed FRGs in COPD group compared with normal group. The significance markers are shown as: *, P<0.05; **, P<0.01; ***, P<0.001. (B) Heatmap of correlation of 15 differentially expressed FRGs.

The GO and KEGG Enrichment Analyses of Differentially Expressed FRGs

To analyze the potential biological functions of these differentially expressed ferroptosis-related genes, we carried out GO and KEGG enrichment analyses by way of R software. In total, 739 biological processes (BPs), 11 cellular components (CCs), 21 molecular functions (MFs) and 26 KEGG pathways were enriched. The GO term results exhibited that differentially expressed FRGs were mainly involved in regulation of smooth muscle cell proliferation, membrane microdomain, membrane raft, caveola, cytokine receptor binding, cytokine activity, and transforming growth factor beta receptor binding. The KEGG analysis indicated that differentially expressed FRGs participated in cell senescence pathway, FoxO signaling pathway and HIF1 signaling pathway (Figure 4A and B, Table 2). After combining with expression levels (logFC), the Z-scores showed that all the significant terms could be positively regulated by differentially expressed FRGs (Z-scores >0) (Figure 4C and D). These findings implied that 15 differentially expressed FRGs may participate in inflammatory responses and airway remodeling in COPD pathogenesis.

Table 2 The Most Significant Terms of GO and KEGG Enrichment Analyses

Figure 4 GO and KEGG enrichment analyses of differentially expressed FRGs. (A) Lollipop plot of significant terms. (B) Circular network of significant terms and genes. Blue nodes represent terms, red nodes represent genes, and connecting lines represent the relationship between terms and genes. (C) Bubble plot of significant terms combined with logFC. A Z-score greater than zero indicates positive regulation, a Z-score less than zero indicates negative regulation, and absolute value of Z-score represents the probability of regulation. (D) Donut plot of significant terms combined with logFC. Each column of the inner circle corresponds to one term, the height of column represents adjusted P value, and the filled color represents Z-score of each term.

Construction of Protein–Protein Interaction (PPI) Network and Identification of Key Module and Hub Genes

To determine the interactive relationship among differentially expressed FRGs, the protein–protein interaction analysis was conducted. The interaction of 15 candidate genes was analyzed in STRING database, and the results were visualized in Cytoscape software. The results showed that these differentially expressed FRGs interacted with each other (Figure 5A) and displayed the interaction number of each gene (Figure 5B, Supplementary Table 1). In total, there existed 15 nodes and 134 edges. The MCODE plugin analysis showed that there existed one key module containing 11 nodes and 50 edges including GDF15, IL6, ATF3, PTGS2, TGFBR1, HIF1A, CDKN1A, ATM, HMOX1, TNFAIP3 and MYB (Figure 5C). The cytoHubba plugin analysis identified five hub genes, including HIF1A, IL6, PTGS2, CDKN1A and ATM (Figure 5D). The Venn diagram indicated the overlap of predicted hub genes (Figure 5E). The detailed information of five hub genes can be seen in Supplementary Table 2.

Figure 5 PPI network, key module and hub genes of differentially expressed FRGs. (A) The PPI among 15 differentially expressed FRGs. (B) The interaction number of each differentially expressed FRG. (C) Key module of the PPI network screened by MCODE plugin. (D) Hub genes screened by cytoHubba plugin. (E) The overlap of predicted hub genes.

Evaluation of Correlation Between Hub Genes and Respiratory Tract Diseases

In order to estimate the theoretical association between predicted hub genes and chemical/environmental exposures, the five hub genes were analyzed in the Comparative Toxicomics Database and four respiratory tract diseases were chosen including COPD, chronic bronchitis, pulmonary emphysema and non-small cell lung cancer (NSCLC). The average inference scores of five hub genes in COPD (46.85) were higher than those in chronic bronchitis (35.72) and pulmonary emphysema (17.17) but lower than those in NSCLC (55.56) (Figure 6). The findings implied that five predicted hub genes might participate in multiple pathophysiological processes in respiratory diseases.

Figure 6 The correlations between hub genes and respiratory tract diseases in comparative toxicomics database.

Construction of the Networks Between Hub Genes with miRNAs, Transcription Factors and Signal Molecules

The hub genes could probably play a role by acting as transcription factors and vital signal molecules or interacting with intracellular non-coding RNAs. In order to predict upstream or downstream molecules of five hub genes and speculate on the mechanism of action of each hub gene, interactive network analysis was conducted. The five hub genes were uploaded to the miRNet online database to analyze the interaction with miRNAs and transcription factors in human lung tissues. In total, 44 miRNAs were predicted and two miRNAs, hsa-let-7b-5p and hsa-miR-1-3p, both targeting five hub genes, were selected for further exploration (Figure 7A, Supplementary Table 3). The transcription factor-hub gene regulatory network consisted of 217 interactions between 164 transcription factors and five hub genes. Five transcription factors including EGR1, NFKB1, RELA, SP1 and STAT3, which had the highest connectivity with hub genes, were selected (Figure 7B, Supplementary Table 3). The ENCORI database was used to screen upstream lncRNAs of the two miRNAs. Six lncRNAs were predicted: NUTM2A-AS19, XIST and NEAT1 (targeting hsa-let-7b-5p); RMRP, MALAT1 and AL162431.2 (targeting hsa-miR-1-3p) (Figure 7C, Supplementary Table 3). Next, five hub genes were uploaded into the NetworkAnalyst database to analyze the interaction with signal molecules. TP53 was prominent due to interacting with three hub genes in a network of signal molecules (Figure 7D, Supplementary Table 3).

Figure 7 The interaction network of hub genes in miRNet and network Analyst. (A) The network of hub genes with miRNAs. (B) The network of hub genes with transcription factors. The fuchsia nodes represent hub genes and the green nodes represent transcription factors. The five transcription factors that connect with at least four hub genes are labelled. (C) The network of hub genes with signal molecules. The signal molecules that connect with at least two hub genes are labelled. (D) The predicted lncRNA-miRNA-hub gene regulatory network. Yellow diamonds represent lncRNAs, green ellipses represent miRNAs, and blue rectangles represent hub genes.

The ROC Curves of Hub Genes

To determine the diagnostic value in discriminating COPD patients from normal controls, the ROC curves of each hub gene were plotted using R software. The logistic regression model of hub genes was constructed based on glm function. The formula was “-88.166 + 3.0089*HIF1A + −2.8988*IL6 + 2.8957*PTGS2 + 3.2435*CDKN1A + 7.3934*ATM”. As shown in Figure 8, the expression levels of HIF1A (AUC: 0.923, CI: 0.804-1.00) and ATM (AUC: 0.976, CI: 0.926-1.000) had high predictive accuracy (Figure 8A and E). The expression levels of IL6 (AUC: 0.826, CI: 0.608-1.000) and CDKN1A (AUC: 0.860, CI: 0.653-1.000) had moderate predictive accuracy (Figure 8B and D). The expression level of PTGS2 had low predictive accuracy (AUC: 0.681, CI: 0.471-0.892) (Figure 8C). The AUC of combination of five hub genes was 0.981 (CI: 0.940-1.000) (Figure 8F). When the cut-off threshold was 1.398, the sensitivity, specificity and Youden index were 0.957, 1.000 and 0.957, respectively. These results indicated that this model had high accuracy and authenticity to distinguish COPD group from normal group.

Figure 8 The receiver operating characteristic (ROC) curves of hub genes. (A) ROC curve of HIF1A. (B) ROC curve of IL6. (C) ROC curve of PTGS2. (D) ROC curve of CDKN1A. (E) ROC curve of ATM. (F) ROC curve of five genes combination.

The Immune Cells Infiltration Characteristics in Patients with COPD and Normal Controls

The infiltrating status of various immune cells in lung tissues had obvious differences (Figure 9A). Monocytes and macrophages accounted for the majority of all infiltrating cells, especially in COPD lung tissues. The infiltration differences in both groups are shown in Figure 9B. Seven types of immune cells, including CD8 T cells, activated NK cells, monocytes, M0 macrophages, M2 macrophages, resting dendritic cells and resting mast cells, had differential infiltration in patients with COPD compared with normal controls. The adjusted P-values of seven kinds of immune cells were 0.002, 0.001, 0.025, <0.001, 0.002, 0.008 and 0.020, respectively. Monocytes and M0 macrophages were upregulated in COPD lung tissues, while CD8 T cells, activated NK cells, M2 macrophages, resting dendritic cells and resting mast cells were downregulated. Figure 10A reveals the correlations between differentially infiltrated immune cells. Monocytes had positive correlations with CD8 T cells, M2 macrophages and resting dendritic cells (r=−0.39, −0.67 and −0.46, respectively). M0 macrophages had inverse correlations with CD8 T cells and activated NK cells (r=−0.38 and −0.58, respectively). However, CD8 T cells had positive correlations with M2 macrophages, resting dendritic cells and resting mast cells (r = 0.54, 0.40 and 0.56, respectively). Resting mast cells were positively associated with M2 macrophages and resting dendritic cells (r = 0.36 and 0.61, respectively). The correlations between the expression of hub genes and differentially infiltrated immune cells are displayed in Figure 10B. Positive associations were observed between monocytes and IL6, monocytes and PTGS2, monocytes and CDKN1A (r = 0.53, 0.42 and 0.62, respectively). M0 macrophages were also positively associated with HIF1A and ATM (r = 0.50 and 0.52, respectively). However, CD8 T cells were strongly negatively associated with HIF1A, IL6, PTGS2 and CDKN1A (r=−0.68, −0.83, −0.72 and −0.79, respectively). The remaining several types of immune cells also had weakly to moderately negative correlations with the expression of most of the hub genes as displayed in the heatmap.

Figure 9 Immune infiltration of COPD lung tissues compared with normal tissues. (A) Stack bar chart of proportions of the immune cells infiltration. (B) Box plot of proportions of the immune cells infiltration. The significance markers are shown as: ns, P>0.05; *, P<0.05; **, P<0.01; ***, P<0.001.

Figure 10 Differentially infiltrated immune cells and hub genes. (A) Heatmap of correlations of differentially infiltrated immune cells. (B) Heatmap of correlations of hub genes with differentially infiltrated immune cells. The significance markers are shown as: *, P<0.05; **, P<0.01.

Discussion

Accumulating evidence indicates that ferroptosis participates in the pathogenesis of COPD. Previous review summarized that ferroptosis can affect inflammation through immunogenicity and ferroptosis inhibitors may benefit certain diseases through their anti-inflammatory effects.2 However, more research is required to better our understanding of ferroptosis in pathogenesis of COPD. In our study, we obtained 15 differentially expressed FRGs in patients with COPD compared with normal controls through bioinformatics analysis. Several hub genes were reported in the previous study. For instance, HIF1A, as a switch gene, was upregulated in COPD cases using network-based analysis implemented by SWIM software.27 CDKN1A played important functions in the development and progression of COPD.28 In our study, the enrichment analyses of 15 differentially expressed FRGs were conducted to explore their potential functions. The results indicated that they were associated with airway inflammatory response and remodeling. For example, cell senescence occurs in many pathological processes in COPD, which is consistent with previous reports. Cell senescence impedes iron-mediated cell death pathways by impairing ferritinophagy, a lysosomal process that promotes ferritin degradation.29

Next, we constructed a PPI network of 15 differentially expressed FRGs and first identified five ferroptosis-related hub genes, including HIF1A, IL6, PTGS2, CDKN1A and ATM. To further explore the correlation between hub genes and diseases, we analyzed the inference scores for four respiratory tract diseases in CTD and found that five hub genes were closely correlated with COPD and other respiratory tract diseases. These findings reminded us that it was vital to clarify the mechanism of action of these genes in COPD pathogenesis.

Bioinformatics methods provide us with a convenient way to predict crosstalk networks and screen potential biomarkers in COPD. A large number of miRNAs and lncRNAs were reported to be involved in COPD initiation and development. MALAT1/miR-146a/COX2 (namely PTGS2) axis affected the lung function of patients with COPD.30 Some non-coding RNA targets including miR-195, miR-181c and TUG1 are viable for alleviating COPD in vivo.31 However, to our knowledge, previous articles reporting the correlation between non-coding RNAs and ferroptosis mainly focused on multiple cancers. The present study constructed the networks of hub genes with miRNAs and transcription factors in miRNet database and identified two key miRNAs, namely, hsa-let-7b-5p and hsa-miR-1-3p. The hsa-let-7b-5p participated in endothelial mitochondrial dynamics and acted as a biomarker for diagnosing Parkinsonian Syndromes.32,33 The hsa-miR-1-3p inhibited lung adenocarcinoma cell tumorigenesis and improved gefitinib resistance in EGFR mutant lung cancer cell.34,35 Additionally, the upstream lncRNAs of two miRNAs were predicted using ENCORI database and we found six lncRNAs with the most experimental evidence. Among them, NUTM2A-AS19 and AL162431.2 are newly reported in this study. XIST and MALAT1 played an important role in mitochondrial dysfunction, cell senescence and epigenetic alterations in COPD pathogenesis under the condition of tobacco smoke exposure.36 NEAT1 promoted activation of inflammasomes in macrophages.37 RMRP promoted the progression of NSCLC via competing with miR-1-3p.38 Thus, we speculate that the following axes may regulate ferroptosis in COPD pathogenesis including NUTM2A-AS19 or XIST or NEAT1/hsa-let-7b-5p/hub gene axes and RMRP or MALAT1 or AL162431.2/hsa-miR-1-3p/hub gene axes. Moreover, the identification of five important transcription factors including EGR1, NFKB1, RELA, SP1 and STAT3 would be the groundwork for molecular mechanisms of ferroptosis in COPD pathogenesis. EGR1 was indispensable for MUC5AC expression induced by cigarette smoke in human bronchial epithelial cells.39 Genetic knockdown of RELA (NFKB subunit) diminished IL6 production in HBE cells.40 SP1 was crucial for anti-inflammatory molecule IL10 secretion in the phototherapy effect in HBE cells.41 STAT3 was a vital molecule in regulating the expression of inflammatory cytokines in COPD murine model.42 Notably, the signal molecule network revealed that TP53 connected with IL6, CDKN1A and ATM, suggesting that TP53 may be a potential driver of COPD towards lung cancer. This indicated that ferroptosis may also participate in COPD-related carcinogenesis.

Previous studies concentrated on the construction of a ferroptosis-related gene model for prognosis in cancer. For example, researchers screened ten ferroptosis-related genes, which served as potential prognostic biomarkers.43 To testify the diagnostic values of hub genes, we conducted ROC analyses and discovered that each of them varied in predictive accuracy, while combination of five genes could serve as a fine model to distinguish patients with COPD from normal controls (AUC: 0.981, CI: 0.940-1.000).

Although immune infiltration in malignancies keeps attracting the attention of researchers, very few reports explored the immune infiltration in COPD. The spatially confined eosinophil-rich type 2 microenvironments were identified in COPD.44 The proportion of T cells decreased in the lungs of current smokers and patients with COPD, whereas the proportion of macrophages increased.45 In our study, we uncovered the immune infiltration status in patients with COPD compared with normal controls. Monocytes were the majority of immune cells in both groups and increased prominently in COPD group. Monocytes, as an essential part of innate immune system, influence human diseases both by direct effects and by differentiating into macrophages.46 The cytokine response of monocytes to bacteria was compromised in smoking-induced COPD and thus impaired immune response.47 Macrophages are plastic in response to various tissue microenvironment and external stimuli. We found that the proportion of M0 macrophages increased markedly, which could serve as reserves ready for polarization stimuli. M1 macrophages primarily take part in pro-inflammatory responses, however, they were not observed to increase remarkably in this study. M2 macrophages, which primarily participate in anti-inflammatory responses, decreased dramatically in COPD group, suggesting that their functions may be undermined in COPD pathogenesis. CD8 T cells were observed to decrease drastically, which was inconsistent with previous researches. The number of IFN-γ-producing CD8+ and CD4+ lymphocytes increased in the lungs of patients with COPD.48 The frequencies of CD8+ T cell subsets increased observably in patients with COPD compared with normal controls and non-smokers.49 It may be partial due to the difference between statistics-based bioinformatics methods and flow cytometry assays. Activated NK cells decreased in COPD lung tissues. However, evidence from other studies revealed that the proportions of NK cells increased in BAL fluid of patients with COPD.50 Another two researches claimed that the number of NK cells in the lung parenchyma of patients with COPD was at the same level as that in the peripheral blood, and bronchoalveolar lavage fluid in healthy smokers.51,52 It seems that NK cells in lung tissues may have different effects compared with those from blood and BALF. Moreover, we found resting dendritic cells and resting mast cells, which were the minority of infiltrating immune cells, decreased in patients with COPD. Dendritic cells present antigens and activate naive T and B cells.53,54 Mast cells can interact with multiple immune cells and structural cells and thereby facilitate inflammatory responses, airway remodeling and angiogenesis.55,56 The functions of them might be antagonized by monocytes and M0 macrophages in some degree in COPD lung tissues. The proportions of monocytes and M0 macrophages were positively associated with most of hub genes, whereas CD8 T cells, activated NK cells, M2 macrophages, resting dendritic cells and resting mast cells were negatively associated most of the hub genes. It can be inferred that the functions of monocyte and M0 macrophages may be promoted by these hub genes. The other types of infiltrating cells, for instance, CD8 T cells, were likely to be inhibited by these hub genes. HIF1A was validated to drive ferroptosis in clear cell carcinomas and ATM was essential for promoting ferroptosis.57,58 IL6 and PTGS2 were confirmed as the downstream markers of ferroptosis.59,60 CDKN1A was required to suppress ferroptosis.61 We speculate that these high-expressed hub genes in COPD group may get involved in the regulation of ferroptosis in structural cells of pulmonary parenchyma and thus affect the infiltrating immune cells residing in pulmonary interstitium or recruited from peripheral blood, which could lead to differentially histopathological changes in the lungs of patients with COPD. Taken together, the immune cells infiltration contributes to the pathogenesis of COPD in a sophisticated manner and more research is in urgent need to elucidate the situation.

Our study had obvious limitations. The number of cases included in our study was relatively small. Due to the lack of detailed clinical information, correlations between hub genes and clinical characteristics cannot be explored. Another apparent deficiency is that we did not perform basic experiments to validate the expression of hub genes and their correlation with immune cells. For now, our study can provide a theoretical basis for further explorations of ferroptosis-related phenotypes in COPD research.

Conclusion

We identified five ferroptosis-related hub genes (HIF1A, IL6, PTGS2, CDKN1A and ATM) in COPD, a combination of which had diagnostic value. Two miRNAs, five transcription factors and one signal molecule were predicted to target these hub genes, and the lncRNA-miRNA-hub gene regulatory network was constructed. Ferroptosis-related hub genes were significantly associated with immune infiltration in the lung tissues of patients with COPD.

Abbreviations

AUC, area under the curve; BP, biological process; CC, cellular component; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CTD, Comparative Toxicomics Database; ENCORI, Encyclopedia of RNA Interactomes; FC, fold change; FRG, ferroptosis-related gene; FVC, forced vital capacity; GEO, Gene Expression Omnibus; GO, Gene Ontology; GOLD, Global Initiative for Chronic Obstructive Lung Disease; GPX4, glutathione peroxidase 4; KEGG, Kyoto Encyclopedia of Genes and Genomes; MCODE, Molecular Complex Detection; MF, molecular function; Nrf2, nuclear factor erythroid 2-related factor 2; NSCLC, non-small cell lung cancer; PCA, principal component analysis; PPI, protein–protein interaction; PUFA-PL, phospholipid containing polyunsaturated fatty acid chain(s); ROC, receiver operating characteristic; ROS, reactive oxygen species; TLR2, toll-like receptor 2.

Ethics Statement

This study was reviewed by Medical Ethics Committee of Qilu Hospital of Shandong University and exempted from ethical approval due to the usage of human data from the open and public Gene Expression Omnibus database.

Funding

This study was supported by the National Natural Science Foundation of China (grant No. 81800039) and the Jinan Clinical Research Center for Prevention and Control Project of Major Respiratory Diseases (grant No. 201912011).

Disclosure

The authors report no conflicts of interest in this work.

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44. Kim SH, Hong JH, Yang WK, et al. Herbal combinational medication of Glycyrrhiza glabra, Agastache rugosa containing glycyrrhizic acid, tilianin inhibits neutrophilic lung inflammation by affecting CXCL2, interleukin-17/STAT3 signal pathways in a murine model of COPD. Nutrients. 2020;12(4):926. doi:10.3390/nu12040926

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52. Eriksson Ström J, Pourazar J, Linder R, et al. Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking. Respir Res. 2018;19(1):244. doi:10.1186/s12931-018-0940-7

53. Freeman CM, Stolberg VR, Crudgington S, et al. Human CD56+ cytotoxic lung lymphocytes kill autologous lung cells in chronic obstructive pulmonary disease. PLoS One. 2014;9(7):e103840. doi:10.1371/journal.pone.0103840

54. Hodge G, Mukaro V, Holmes M, Reynolds PN, Hodge S. Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway. Respirology. 2013;18(2):369–376. doi:10.1111/j.1440-1843.2012.02287.x

55. Freeman CM, Curtis JL. Lung dendritic cells: shaping immune responses throughout chronic obstructive pulmonary disease progression. Am J Respir Cell Mol Biol. 2017;56(2):152–159. doi:10.1165/rcmb.2016-0272TR

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60. Chen PH, Wu J, Ding CC, et al. Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism. Cell Death Differ. 2020;27(3):1008–1022. doi:10.1038/s41418-019-0393-7

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Airway Management Devices Market Outlook 2031

  • The global airway management devices market was valued at US$ 1.1 Bn in 2021
  • The global market is projected to expand at a CAGR of 7.7% from 2022 to 2031
  • The global airway management devices market is anticipated to reach US$ 2.3 Bn by the end of 2031

Analysts’ Viewpoint on Airway Management Devices Market Scenario

The global airway management devices market is majorly driven by rise in prevalence of chronic respiratory diseases across the globe. Strategic acquisition & collaborative agreements between key players and small players in emerging markets such as India, increasing geriatric population, rising incidences of preterm births, and corresponding efforts to improve survival rates are contributing to the market growth. However, companies in the global airway management market should focus on developing cost-efficient devices for the patients. Moreover, as patient admissions to emergency care departments and ICUs increased due to the COVID-19 pandemic, healthcare centers have become cautious and are procuring respiratory devices to address demand during pandemic-like situations in the future.

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Overview of Airway Management Devices Market

According to the latest report published by Transparency Market Research, the global airway management devices market is projected to expand at a considerable growth rate from 2022 to 2031, due to rising prevalence of chronic respiratory diseases such as asthma and COPD globally.

Patients with severe respiratory infections or low oxygen saturation often require positive air pressure devices such as ventilators. Airway management equipment include airway management tubes (endotracheal tube), laryngoscope handle and blade, positive airway pressure devices, and various sized oropharyngeal airways. These devices are mainly used in operating rooms during surgeries. In addition, for better patient outcomes, leading players operating in the global airway management devices market are focusing on developing technologically advanced respiratory devices.

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Rise in Prevalence of Respiratory Diseases Globally to Fuel Airway Management Devices Market Growth

Increase in incidences of chronic respiratory diseases such as asthma, and chronic obstructive lung disease (COPD) is driving the demand for airway management devices. Chronic obstructive pulmonary diseases, bronchitis, and emphysema, lung cancer, neoplasms of the respiratory tract, etc., significantly affect airways and lung structures. The incidence of respiratory diseases is increasing due to environmental and lifestyle-related factors such as air pollution, smoking habits, sedentary lifestyles, and stress. Rise in the number of patients suffering from such diseases, and rapid introduction & availability of portable, cost-contained, and easy-to-use airway equipment for the treatment of such conditions drive demand for airway management devices. Airway stenting and airway clearance system are unique therapy systems that use airway management devices.

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According to the World Health Organization (WHO), in 2019, over 65 million people suffered from chronic obstructive pulmonary disease (COPD), and 3 million succumbed to it, making it the third-leading cause of death globally. Over 80% of these deaths occurred in low- and middle-income countries (LMIC). Over 262 million people suffer from asthma, the most common chronic pediatric disease that affects 14% of all children globally every year. In 2020, around 10 million people developed tuberculosis (TB) and 1.4 million lost their lives, making it the most common lethal infectious disease. Lung cancer accounts for 1.6 million deaths each year and is the most lethal form of cancer. Globally, 4 million people die prematurely from chronic respiratory disease. At least 2 billion people are exposed to indoor toxic smoke, 1 billion inhale outdoor pollutants in the air, and 1 billion are exposed to tobacco smoke.

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Increase in Adoption of Technologically Advanced Infraglottic Devices

In terms of product type, the global airway management devices has been classified into supraglottic device, infraglottic device, resuscitators, and laryngoscope. Infraglottic devices are expected to account for a dominant share of the global market in the upcoming years. Tracheostomy tubes and endotracheal Tubes (ETTS) are some of the popular infraglottic devices used by patients. Technological advancements in these devices and their increasing application during emergencies are major factors fueling the demand for infraglottic airway devices, particularly in developed regions such as Europe and North America.

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CUMBERLAND, Md., May 23, 2022 (GLOBE NEWSWIRE) -- RS BioTherapeutics, whose mission is to harness its strong and thorough understanding of the endocannabinoid system to research, develop and commercialize interventions to address chronic and acute pulmonary (lung) inflammation-based diseases, is pleased to announce that is has entered into a license agreement with Synthonics, Inc. for the exclusive, worldwide right to use Synthonics’ metal coordinated cannabinoid in nebulized form for the treatment of pulmonary inflammatory disorders. RS BioTherapeutics is developing its lead compound, RSBT-001, as both an alternative and a complement to corticosteroids for the treatment of chronic obstructive pulmonary disease (COPD).

COPD is a chronic inflammatory lung disease that causes obstructed airflow from the lungs and includes emphysema, chronic bronchitis, asthma and more. According to the American Lung Association, 156,045 people died from COPD in 2018, making it the third highest disease-related cause of death behind heart disease and cancer. It is estimated that more than 250 million people globally may have the condition and more than 65 million people around the world have moderate or severe COPD. Experts predict that this number will continue to rise worldwide over the next 50 years. The CDC estimates that 16 million Americans suffer from COPD. People with COPD are at increased risk of developing heart disease, lung cancer, and a variety of other conditions. If chronic pulmonary inflammation is untreated, it can lead to fibrosis, organ damage, and loss of organ function.

Commenting on the potential benefits of this first investigational compound, RSBT-001, Justin Molignoni, CRNP, Chief Strategy Officer and Co-Founder of RS BioTherapeutics, said, “Alternatives to corticosteroids are needed for people with chronic inflammatory diseases. We believe RSBT-001 has the clinical potential to address exacerbation and prevent progression of both acute and chronic pulmonary inflammation related to respiratory diseases including COPD, SARS-COV-2, Cystic Fibrosis, Asthma, Bronchitis, and Acute Respiratory Distress Syndrome.”

John Tinkham, CEO and Co-Founder of Synthonics, added, “We believe that metal coordination can significantly enhance the effectiveness of cannabinoid-based pharmaceuticals and are delighted to partner with RS BioTherapeutics on this project. We look forward to working closely with RS BioTherapeutics to assist on the development of RSBT-001.”

Various sources estimate the global pulmonary drug delivery systems market was approximately $51 billion in 2021, and it is expected to be worth around $92 billion by 2030, with a compound annual growth rate of 6.6 percent within in next 10 years.

About RS BioTherapeutics Founded by experts in pulmonary diseases and the endocannabinoid system, RS BioTherapeutics is a wholly owned subsidiary of Real Science Holdco LLC. The company’s mission is to harness its strong and thorough understanding of the Endocannabinoid System in the research, development, and commercialization of forward-thinking interventions to address chronic and acute pulmonary inflammation-based diseases.   More information on RS Biotherapeutics can be found at www.rsbiotherapeutics.com.

About SynthonicsSynthonics, Inc. is a privately-held specialty pharmaceutical company focused on the discovery and development of patentable drugs that incorporate its proprietary metal coordination chemistry. It binds metals to known pharmaceutical agents to create new products that are better absorbed and thus have greater therapeutic benefits than their predecessors. More information on Synthonics can be found at www.synthonicsinc.com.

Media Contact: David Gutierrez, Dresner Corporate Services, (312) 780-7204, [email protected]

 

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The infection rate of SARS-CoV-2, the virus that causes COVID-19, is 24 times higher in laboratory cultured respiratory cells from humans with chronic obstructive pulmonary disease (COPD) than in those from healthy people, a study shows.

This increased susceptibility to infection, which makes severe outcomes more likely, was associated with higher enzyme levels that the virus uses to penetrate cells, as well as higher pro-inflammatory molecular levels and lower levels of antiviral proteins.

“Together, these results have enabled us to understand the mechanisms behind increased COVID-19 susceptibility in COPD patients,” said Phil Hansbro, PhD, the study’s senior author in a Press release. Hansbro is Professor of Microbiology at the University of Newcastle and Director of the Centenary UTS Center for Inflammation, both in Australia,

“We believe in the new [therapies] Targeting relevant enzymes and pro-inflammatory responses in SARS-CoV-2 infection could have excellent therapeutic potential to reduce the severity of COVID-19 in patients with COPD, ”added Hansbro.

The study, “Increased SARS-CoV-2 infection, protease and inflammatory responses in COPD primary bronchial epithelial cells defined by single cell RNA sequencing“was published in American Journal of Respiratory and Critical Care Medicine.

Mainly associated with prolonged exposure to irritants such as cigarette smoke, COPD is characterized by excessive airway inflammation, pulmonary tissue remodeling and the progressive destruction of the alveoli – the small lung air sacs responsible for gas exchange.

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Rising evidence shows COPD patients are more susceptible to severe COVID-19, but the underlying mechanisms of this susceptibility remain largely unclear.

One potential factor is the increased production of ACE2 – the cell surface receptor that SARS-CoV-2 binds to enter cells – in airway cells after exposure to cigarette smoke. Also, COPD patients’ lungs have higher than normal levels of proteases, a family of enzymes that include those used by SARS-CoV-2 to penetrate cells.

To learn more about what contributes to COPD patients’ increased susceptibility to SARS-CoV-2 infection, Hansbro’s research team, together with colleagues in Australia, analyzed the viral load and gene activity profiles of laboratory-grown airway cells – called primary bronchial epithelial cells (pBECs) – from four adults. with COPD and three healthy adults using a high-resolution technique called single-cell RNA sequencing.

Patients included two women and two men (age range, 67-85 years), while healthy controls included two women and one man (age range, 55-75 years). No participant had a history of respiratory infection within the past month or a lung cancer diagnosis.

The results showed that seven days after cells were exposed to SARS-CoV-2, “there was a 24-fold increase in the amount of virus in the COPD patient’s airway cells compared to the cells taken from healthy individuals,” Matt Johansen, PhD, the study’s first author from Centenary UTS Center for Inflammation, said.

Gene activity profiles between infected and present cells in both groups were generally similar, highlighting that “there are commonly used pathways in SARS-CoV-2 [infection]which are independent of pre-existing disease status, ”the researchers wrote.

Compared with controls, airway cells from COPD patients showed significantly increased levels of transmembrane protease serine 2 (TMPRSS2), cathepsin B (CTSB) and cathepsin L (CTSL), three proteases known to promote the entry of SARS-CoV-2 into cells.

In turn, the levels of more serpins – proteins known to suppress the activity of proteases – were significantly reduced in COPD cells compared to healthy controls, regardless of infection.

These results “highlight a protease imbalance in COPD-pBECs that may be crucial for increased SARS-CoV-2 infectivity and serious disease,” the researchers wrote.

“Simply put, milder and increased cell infection makes it far more likely that people with COPD will have more serious disease outcomes,” Johansen said.

The team also found that the levels of pro-inflammatory molecules associated with COPD’s sudden disease aggravating episodes and severe COVID-19 were significantly increased in both infected and uninfected respiratory cells from people with COPD.

“COPD is an inflammatory disease in which patients have increased inflammation… compared to healthy people,” and “it is highly likely that SARS-CoV-2 exacerbates this existing high level of inflammation, leading to even worse outcomes,” Johansen said.

Key antiviral responses involving proteins called interferons were also largely blunt-ended in respiratory cells from COPD patients compared to those from controls, which may be “a key driver for increased susceptibility to elevated inflammatory and viral responses. [infection]”, wrote the research team.

ACE2 was found to be significantly increased by infection in both COPD and control cells, but there were no significant differences between the groups, suggesting that ACE2 may not be a contributing factor to increased infection susceptibility in COPD.

In addition, therapeutic interventions that suppress either TMPRSS2, CTSB, inflammation, or all three at the same time significantly reduced SARS-CoV-2 load and pro-inflammatory molecules in especially COPD patient cells.

This is the “first study to show biological evidence that COPD pBECs are significantly more tolerant of SARSCoV-2 infection compared to healthy pBECs,” the researchers wrote.

The results also highlighted that this increased susceptibility is due to protease imbalances, major inflammatory responses, and reduced interferon responses, potentially describing “biological mechanisms responsible for exacerbations and severe COVID-19 in COPD,” the research team wrote.

Several studies are needed to analyze the relevance of these candidates, as well as the therapeutic potential of targeting protease imbalance, excessive inflammation, or deficient interferon response in COPD patients with COVID-19.

Hansbro said these findings are critical as hundreds of millions of people are affected by COPD globally and COVID-19 is likely to exist in the coming years.



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MCCALLA... I was fine. I was enjoying my life, preparing to travel to just live my life and then I took the vaccine and I found out the worse news of my life. But, I’m actually thankful I took the vaccine because if I didn’t I would’ve found out when it’s way to late, at least now I have a fighting chance.

Labelled as a medical mystery after being diagnosed with stage four lung cancer, 26-year-old Kimberley McCalla is hoping the GoFundMe account she launched will give her the US$16,000 needed to start targeted therapy, the ideal treatment for her illness, her doctors have advised.

“For the treatment, they want to do targeted therapy, and it is very expensive — 30 tablets is US$16,000. The US$16,000 is just to start me off to see how far I can get on it in terms of sourcing the medication and starting. My aim is to reach my goal on the GoFundMe so that I can get started with that treatment as soon as possible,” she said, suggesting that to date she has raised over US$5,000.

At first, blaming her symptoms on the COVID-19 AstraZeneca vaccine she took last year August, McCalla now strongly believes that if she did not take the vaccine she would have found out about her diagnosis when it was way too late.

“I took my first dose on August 3 and then I got sick. I had a prolonged fever and I had shortness of breath and some back pain. I noticed that it wasn’t going away so I went to my private doctor and she gave me an asthma pump and that did help with the shortness of breath but it was still progressing. I noticed that something was wrong. I was wondering if it was the vaccine because of all the rumours going around with the vaccine,” McCalla told the Jamaica Observer.

Noting that she had no prior symptoms before taking the vaccine, McCalla said she was still a bit “delusional” that it was the cause of her illness, but when she was told the hard truth about her terminal illness, she knew she had to face the facts.

“I was fine. I was enjoying my life, preparing to travel to just live my life and then I took the vaccine and I found out the worse news of my life. But, I’m actually thankful I took the vaccine because if I didn’t I would’ve found out when it’s way to late, at least now I have a fighting chance,” McCalla stated.

However, after her symptoms would not subside, she recalled seeking additional medical help and an X-ray of her chest was done. A mass was discovered on her chest, and her doctor referred her to the University Hospital of the West Indies where a series of tests were completed, including a biopsy. Then, on September 16 she was told that the mass was cancerous and it had already spread to her back, explaining her persistent back pain.

In addition to the back pain, McCalla said she had difficulty breathing, resulting in her needing a wheelchair because she could not walk or do any activity for an extended time. The shortness of breath, McCalla said, was due to fluid build-up in her lungs, another sure sign that the cancer was aggressive.

“They were rushing to get me on chemotherapy because not only was I sick with the cancer, but there’s fluid on my chest, which prevents me from walking long distances and basically doing anything in terms of exhaustion,” she said, confirming that she was unable to do the chemotherapy until December because of financial constraints.

In the meantime, McCalla said her doctors managed her symptoms with medication and periodically drained the fluid from her lungs to aid in her breathing.

“I started chemotherapy in December, but then I got COVID and I was hospitalised. I was even placed on oxygen and I swear I didn’t know I was going to make it, being that I had such a terminal illness and then I had COVID. They kept me there until everything was okay enough for me to go home. So, from December until now I’ve been on chemotherapy. I had not made much progression in terms of the fluid on the chest because I still can’t walk long distances,” the fashion entrepreneur said, adding that due to her illness she had to put her business, Gormc Designs, on hold because she’s unable to manage it.

In an attempt to discover the cause of her lung cancer, McCalla said the doctors conducted a number of tests, but to no avail.

“The term that they are using is that it’s a medical mystery because they did several tests, they even did a genetic test to see if it can skip like a thousand generations and then it come to me, it showed that there’s nothing there that would be conclusive of what's happening now,” she said, adding that she is not a smoker and she has never been around smokers for long periods of time.

“Doing this GoFundMe and putting myself out there, I just want to be a source of inspiration to use my story to highlight many things, not just God and how great he is, but as well as lung cancer and how smoking is dangerous. I see it every day where persons smoke around their kids, with no regard for their health or anything and then when it reach to a stage where you have something like this everyone is regretful but no one is taking responsibility for the initial action,” McCalla continued, while expressing her gratitude to her family for their support.

Persons interested in assisting McCalla may visit her GoFundMe account using the following link: gofund.me/cd17851e or by visiting the website and search for Help Kimberly Cancer Treatment.



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Introduction

Chronic obstructive pulmonary disease (COPD) claimed more than 3 million lives in 2019 and is now the third leading disease-related cause of death globally, according to the World Health Organization.1 Long-term exposure to tobacco smoke is the most common cause of the disease in the industrialized world, and results in persistent airflow limitation, due to chronic inflammation and remodeling of the airways.2 However, this inflammation is not confined to the airways. Signs of systemic inflammation are also present and are associated with comorbidities of COPD, such as type 2 diabetes mellitus (T2DM).3 Notably, the pathologic glucose homeostasis in T2DM is related to signs of systemic inflammation and this is also true for metabolic syndrome (MetS), another common metabolic comorbidity in COPD.4–7 Furthermore, the prevalence of COPD is increased in patients with T2DM, even after adjustment for risk factors that predispose to both these diagnoses.8,9 In a similar manner, there is evidence that COPD is more prevalent among patients with MetS.10 Despite an expanding body of evidence that clinically relates COPD with T2DM and MetS, there is poor understanding of the underlying pathogenic mechanisms linking these diseases. We reasoned that a more comprehensive characterization of these mechanisms may reveal novel targets for diagnosis or therapy in COPD and metabolic comorbidities.

Excessive mobilization of neutrophils, including both recruitment and activation, is a common and prominent sign of systemic inflammation in COPD.11–13 Interestingly, this type of inflammation is observed in T2DM and MetS as well, and may therefore constitute a unifying pathogenic mechanism in COPD patients with either of these comorbidities.14,15 Specifically, neutrophils comprise the most abundant subset of leukocytes in blood, and are important players in antibacterial host defense and in repair of tissue injury.16,17 Under normal conditions, their mobilization is carefully regulated by numerous mediators, including interleukin-6 (IL-6), IL-8 and interferon-γ (INF-γ).18–21 Moreover, neutrophil products, such as serine proteinases and gelatinases, exert important anti-bacterial functions and regulate inflammation, through proteolytic modification of several cytokines, including IL-6, IL-8 and members of the IL-36 family.16,22,23 Systemic IL-6 is increased and correlates in a positive manner with insulin resistance in patients with COPD,24 which is compatible with excessive neutrophil mobilization constituting a contributing factor. Along the same lines, systemic IL-8 is enhanced in patients with COPD, T2DM and MetS combined with heart failure.25–27 Notably, it was recently demonstrated that certain members of the IL-36 family are involved in local and systemic inflammation in COPD and that these cytokines exert pro-inflammatory effects on neutrophils.28–33 Intriguingly, systemic IL-36γ correlates in a negative manner with glycated hemoglobin (HbA1c) and fasting glucose in obese patients with T2DM.28,34

In parallel with its central role in innate immunity, neutrophil mobilization facilitates the production of cytokines that modulate adaptive immunity, such as C-X-C motif chemokine ligand 10 (CXCL10, also known as interferon-γ-inducible protein 10 or IP-10).16,35,36 It therefore seems rational that the concentration of CXCL10 is increased in the airways of patients with COPD, in particular during exacerbations.37 At the same time, there is evidence that elevated systemic CXCL10 may predispose to development of T2DM.38

The fact that several signs of increased neutrophil mobilization are evident in COPD, T2DM and MetS led us to hypothesize that there is an altered glucose homeostasis in COPD, associated with an increased mobilization of neutrophils. We addressed this hypothesis in a pilot study on current long-term smokers with and without COPD plus a control group of healthy non-smokers. In these subjects, we assessed alterations in glucose homeostasis by quantifying blood glucose after overnight fasting and during an oral glucose tolerance test (OGTT). Furthermore, we characterized neutrophil mobilization in the airways and in blood by determining concentrations of neutrophils, functionally related cytokines and proteinases. Finally, we quantified the concentration of C-reactive protein in blood as a reference for systemic inflammation.

Materials and Methods

Human Study Population and Ethics

We utilized the human study population “KOL-KB 2011”, including healthy non-smokers (HNS), long-term smokers without COPD (LTS) and long-term smokers with COPD (LTS+COPD). The study population was recruited in accordance with the ethical principles of the World Medical Association (the Helsinki Declaration). The study protocol was approved by the Regional Ethical Review Board in Gothenburg, Sweden (Diary No. 968–11). All subjects provided oral and written informed consent prior to study participation. Some data from this study population have previously been published, although in a different scientific context.28,39,40

Recruitment

Screening Visit

The subjects were identified through an advertisement in the regional press or through their contact with the outpatient clinic at the Department of Respiratory Medicine and Allergy, Sahlgrenska University Hospital in Gothenburg, and were then invited to a screening visit. During that visit, the clinical history and the smoking habits of the subjects were recorded, and a physical examination was performed. Height and weight of each subject were measured, and body mass index (BMI) was calculated. In parallel, percutaneous oxygen saturation was determined with a pulse oximeter. Blood tests included hemoglobin (Hb), coagulation parameters, a standard panel of specific Immunoglobulins E (IgE) against common inhaled allergens (Phadiatop®, PhadiaTM, Uppsala, Sweden) and viral serology (hepatitis B and C, HIV). In addition, premenopausal female subjects underwent a testing to exclude ongoing pregnancy.

Ventilatory lung function was assessed using dynamic spirometry with reversibility test and gas exchange was assessed with diffusion capacity for carbon monoxide (DLCO).41,42 The screening visit also included an electrocardiogram (ECG) and a standard chest X-ray, performed, respectively, at the Department of Clinical Physiology and the Department of Radiology at Sahlgrenska University Hospital.

Inclusion Criteria

A negative history of asthma and atopy (with the exception of contact allergy to nickel) was required for all subjects, as well as negative Phadiatop test, negative viral serology and negative pregnancy test, when applicable. Subjects with BMI ≥ 35 kg/m2 or body weight >100 kg were excluded, to ensure medical safety during the bronchoscopy investigation, which was performed for research purposes only. Furthermore, we did not accept more than three respiratory tract infections during the last year. We also required absence of any signs of infection during the screening visit and an infection-free period of at least four weeks prior to the bronchoscopy visit; otherwise, the corresponding visit had to be re-scheduled. We accepted patients with previously diagnosed, compensated cardiac failure, osteoporosis and cured cancer disease (>5 years prior to the inclusion), along with well-treated hypothyroidism, epilepsy, depression and hypertension. No other established diagnoses were accepted, including T2DM, MetS and obstructive sleep apnea (OSA). Subjects on regular treatment with statins, inhaled corticosteroids and/or long-acting inhaled bronchodilators, including both beta-2-agonists and anticholinergics, were excluded. In a similar manner, a regular treatment with immunosuppressive or anti-inflammatory medication was not accepted. Exceptions to this criterion were NSAID and oral steroids when a mandatory wash-out period of four weeks prior to bronchoscopy could be ensured. However, paracetamol treatment was allowed with no restrictions.

Subjects in the HNS group were required to have a negative history of smoking and of lung disease, in addition to a normal chest X-ray and dynamic spirometry indicating normal lung function after bronchodilation (three doses of inhaled terbutaline; 0.5 mg/dose; Bricanyl TurbuhalerTM, AstraZeneca Ltd, Södertälje, Sweden), in terms of forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio ≥0.70 and FEV1 > 80% of predicted (reference values: European Community for Steel and Coal).41 One included subject in this group had an FEV1/FVC ratio of 0.68, but this subject displayed large lung volumes (FEV1: 106% of predicted, FVC: 127% of predicted) and lacked both clinical and historical signs of lung disease, thus was classified as not having COPD.

Subjects classified as long-term smokers had to meet the requirements of active tobacco smoking of ≥5 cigarettes per day, during the last 5 years, and of a historic tobacco load of ≥20 pack-years. For all long-term smokers, we accepted the presence of chronic bronchitis, defined according to standard criteria.43

The spirometry criteria for inclusion in the group of LTS were a post-bronchodilatory FEV1/FVC ratio ≥0.70.

Subjects in the LTS+COPD group were required to have an FEV1/FVC ratio <0.70 after bronchodilation, corresponding to the criteria for GOLD stage I–III as of 2011.44 For safety reasons related to the bronchoscopy investigation, it was required that all subjects had FEV1 ≥1.0 liter (L), DLCO ≥50% of predicted and percutaneous oxygen saturation >93%. Notably, history and radiological signs of chronic bronchitis and emphysema were accepted in LTS+COPD. This was the only study group also allowed to have an “as needed” treatment with short-acting inhaled beta-2-agonists and/or short-acting inhaled anticholinergics, with a prerequisite of a three-day wash-out prior to bronchoscopy.

Among the included study subjects, one subject in the LTS group attended but did not complete the bronchoscopy, due to poor compliance during this investigation. Consequently, only blood samples were harvested from this subject on the bronchoscopy visit. Moreover, one subject in the LTS+COPD group withdrew from the study prior to the bronchoscopy visit, for personal reasons. Thus, the absence of the certain samples for these two subjects is reflected by the varying n for the different outcomes of the relevant study groups.

Glucose Measurements

The concentration of glucose was assessed during the screening visit, in capillary whole blood harvested from a fingertip with a glucose meter (Freestyle Freedom Lite®, Abbott Diabetes Care Inc., Alameda, CA, USA). Each concentration was measured in doublets and the corresponding average value was used in further analysis. An initial sampling was performed after overnight fasting for 10 hours (hrs) and was followed by an oral glucose tolerance test (OGTT) with 75 grams (g) (200 milliliter (mL)) of a commercial glucose solution (Gluco® 75, TruLaboratories Corporation®, Cubao, Quezon City, Philippines) in accordance with standard clinical routines. The OGTT was finalized after 120 minutes (min), when a second sampling was performed to determine the concentration of capillary blood glucose at the end of OGTT. Accordingly, the change in glucose concentration during OGTT was estimated by the difference in glucose concentration between the end of OGTT and fasting.

Bronchoscopy Visit

Blood Samples

Peripheral venous blood (60 mL) was collected after overnight fasting, prior to bronchoscopy as whole blood (1x4 mL), plasma (4x4 mL) and serum (4x10 mL). A more detailed protocol for the sample collection, process and analysis has been described elsewhere.39

Briefly, the whole blood sample was used to determine the concentration of hemoglobin (Hb), total leukocyte concentration (LPC) and blood cell differential counts, in accordance with accredited standard procedures (Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden). The samples intended for the harvesting of plasma and serum were centrifuged (1500 revolutions per min (rpm); 443 gravitational acceleration (g); 10 min at room temperature (RT)), and the acquired plasma and serum samples were frozen (−80 degrees Celsius (°C)) for future analyses.

Quantification of C-Reactive Protein

C-reactive protein (CRP) in serum was quantified in an accredited laboratory (Department of Clinical Chemistry at Sahlgrenska University Hospital). In brief, we utilized a high sensitivity method (CRPHS; Roche/Cobas, No. 04628918190; Roche Diagnostics Scandinavia AB, Solna, Sweden) based upon the agglutination of CRP to latex particles exposed to anti-CRP antibodies and the detection of the formed compounds by a turbidimetric analysis instrument (Cobas® 8000 Roche Diagnostics Scandinavia AB, Solna, Sweden).

Quantification of Cotinine

The nicotine metabolite cotinine was quantified in serum with a competitive immunochemical method (Immulite 2000 XPi Nicotine metabolite; No. L2KNM2 (200 test); Siemens Medical DiagnosticTM, Siemens Healthcare, Upplands-Väsby, Sweden), utilizing a chemiluminescence detector (Immulite 2000 XPi®; Siemens Medical DiagnosticTM, Siemens Healthcare, Upplands-Väsby, Sweden) in an accredited laboratory (Department of Clinical Chemistry at Sahlgrenska University Hospital).39

Bronchoscopy

An experienced specialist in respiratory medicine performed the bronchoscopy during stable clinical conditions and according to the clinical routines at Sahlgrenska University Hospital, as described in detail elsewhere.39 In brief, the study subject was premedicated with ketobemidone hydrochloride (KetoganTM; <7.5 mg intramuscularly or <5 mg intravenously; Apoteket, Solna, Sweden) and local anesthesia with lignocaine (nebulized XylocaineTM 10 mg/dose; oropharyngeal administration of 2 doses, up to 3 times; Apoteket, Solna, Sweden). A flexible bronchoscope was then inserted through the oral cavity into the lower airways and wedged in a segmental bronchus (lingula or middle lobe), while administrating additional local anesthesia through the instrument as needed. Subsequently, a lower airway sample was harvested (either a protected bronchial brush or a BAL sample) and transferred to a sterile tube, which was stored at 4°C, until being transported to an accredited laboratory for further analysis (Department of Microbiology at Sahlgrenska University Hospital). The bronchoscope was then wedged in another segmental bronchus and three portions of 50 mL (a total of 150 mL) phosphate-buffered saline (PBS) at 37°C were instilled into the airways. Bronchoalveolar lavage (BAL) samples were aspirated after each instillation, pooled in a plastic container (SERRES® Polypropylene measuring cup 250 mL, No. 6057257; Mediplast AB, Malmö, Sweden) and kept on ice until further processing at the laboratory.

BAL Samples

The BAL samples were processed as previously described in detail.39 In brief, cells and extracellular fluid were separated from debris by filtration (Woven mesh spacers, Dacron® 124 mm diameter, No. AP3212450; Merck Chemicals and Life ScienceTM AB, Solna, Sweden). Cells were then pelleted by centrifugation (1400 rpm; 378 g; 10 min at 4°C). A second centrifugation (2000 rpm; 771 g; 10 min at 4°C) of the cell-free BAL fluid (BALF) was performed to eliminate any carry over debris before storage at −80°C. After been re-suspended in PBS, the cell pellet was transferred to a Bürker counting chamber to determine the total cell concentration. Türk´s solution (Cat. No. 93770, Sigma-Aldrich Sweden AB, Stockholm, Sweden) was utilized to assess cell viability. Differential cell counts were performed accordingly. Two cell suspensions (100 microliters (µL) of 600 cells/µL each) were loaded on cytospin slides and centrifuged (1000 rpm; 246 g; for 5 min at RT in Cytospin™ 4, Thermo Fisher Scientific™, Shandon, MA, USA). The slides were then air-dried (overnight) and stored frozen (−20°C) prior to May-Grünwald-Giemsa staining and cell counting (200 cells per sample) under a light microscope.

Laboratory Investigations

Quantification of Cytokines

The protein concentrations of IL-6, IL-8, INF-γ and CXCL10 were determined in BALF and plasma from peripheral blood, utilizing the U-Plex assay® (Meso Scale DiscoveryTM platform, cat no K15067-L1, Meso Scale Diagnostics, Rockville, Maryland, USA) in accordance with the manufacturer’s recommendations, as previously described.40

The protein concentrations of the IL-36 family of cytokines, including IL-36α, -β and -γ, were quantified in both BALF and plasma samples, utilizing commercial DuoSet ELISA kits (R&D Systems, Minneapolis, MN, USA) as previously described.45,46

Quantification of Neutrophil Elastase

The protein concentration of neutrophil elastase in BALF was determined using a commercial sandwich ELISA (Human PMN Elastase ELISA; No. 191021100; BioVendor® Laboratorni Medicina A.S., Brno, Check Republic) according to the manufacturer’s instructions, as described elsewhere.39 Data on neutrophil elastase has been previously published for a subgroup of the utilized study population, although in a different scientific context.39

Quantification of Net Gelatinase and Net Serine Proteinase Activity

The net proteolytic activity of gelatinase and serine proteinases was determined in BALF utilizing a fluorometric method, as described elsewhere.47 Briefly, fluorescein labeled dye-quenched (DQ) gelatin and elastin EnzChek® molecular probes were incubated with the BALF (at 37°C for 16 hrs). The fluorescence intensity was then assessed with a multimode microplate reader (CLARIOStar®; BMG Labtech Pty. LtdTM, Ortenberg, Germany), set at 495 nm as absorption maximum and 515 nm as emission maximum. Increasing values of fluorescence intensity corresponded to increasing net activity of gelatinase and serine proteinases. A subset of this data has been previously published in a different scientific context.39

Bacteria in the Airways

The growth of aerobic bacteria was determined in the lower airways of each subject by performing a qualitative and quantitative analysis of samples from this compartment, following standard laboratory procedures as previously described.39 Briefly, a morphological analysis was performed to assess the percentage of squamous epithelial cells in the samples, and a percentage less than 1% was required to judge a sample as representative for the lower airways. Mass spectrometry (MALDI-TOF) was used to identify and quantify (if >100 colony-forming units (CFU)/mL) the 10 most common bacterial species in each of the samples that were judged representative for the lower airways. However, in the samples that were judged as non-representative for the lower airways, MALDI-TOF was utilized to identify and quantify (if >1000 CFU/mL) the potential pathogenic bacteria only.

Statistics

We applied non-parametric statistical analyses using GraphPad Prism 9.0.1 (GraphPad Software, San Diego, CA, USA). Given the limited statistical power of the material, the statistical analysis of group differences was restricted to the groups of LTS+COPD and HNS. In this sense, here, we utilized Mann–Whitney U-test for group comparisons of continuous variables. Correlation analysis was conducted with Spearman’s rank correlation test and was initially performed in the LTS+COPD group. The statistically significant correlations in this group were then expanded to the groups of LTS and HNS, given the limited statistical power in our study material. A p-value <0.05 was regarded statistically significant.

Results

Human Study Population

The principal clinical characteristics of the included subjects are summarized in Table 1. More specifically, we detected no pronounced differences for age, gender or BMI among the three study groups. The LTS and LTS+COPD groups had very similar exposure to tobacco smoke, in terms of current (cigarettes/day) and historic (pack-years) tobacco smoking, as well as of cotinine concentration in serum. The LTS+COPD group displayed clearly lower FEV1 (% of predicted) and FEV1/FVC ratio compared to the HNS and LTS groups, which is consistent with the study´s inclusion criteria. The concentrations of CRP and Hb in blood were not markedly different among the three study groups. As expected, regular pharmacological treatment was more frequently observed at screening visit in the groups of long-term smokers (LTS and LTS+COPD) compared to HNS. Antidepressants and hypnotic drugs were the most common medications in the two groups of long-term smokers but were not used in the HNS group.

Table 1 Clinical Characteristics of the Human Study Population

Table 2 presents the baseline characteristics of BAL and blood samples. Data on neutrophil concentrations are presented more in-depth below, in the section “Neutrophil concentrations in long-term smokers with COPD”.

Table 2 Characteristics of Blood and BAL Samples

Notably, the bacteriological analysis in samples from the lower airways revealed growth of airway pathogens in HNS mainly and less in LTS, while no such pathogens were detected in LTS+COPD (Table 3).

Table 3 Bacteriological Findings in the Lower Airways

Glucose Homeostasis in Long-Term Smokers with COPD

The LTS+COPD group displayed a lower concentration of fasting blood glucose and a more pronounced change in blood glucose during OGTT compared with the HNS, and these differences were statistically significant (Figure 1A and B). The concentration of blood glucose at the end of OGTT tended to be elevated in the LTS+COPD compared to the HNS group, though this difference did not reach statistical significance (Figure 1C).

Figure 1 (A) Concentration of fasting blood glucose (n= 6–11), (B) change in blood glucose concentration during OGTT (n= 6–11) and (C) concentration of blood glucose at the end of OGTT (120 min) (n= 6–11) measured with a glucose meter in capillary blood of HNS, LTS and LTS+COPD.

Abbreviations: OGTT, oral glucose tolerance test; HNS, healthy non-smokers; LTS, long-term smokers without COPD; LTS+COPD, long-term smokers with COPD.

Notes: Data are presented as observed and as median values. See “Material and methods” regarding the utilized assays. In all three graphs, group comparisons were restricted between the groups of LTS+COPD and HNS, and were performed using the Mann–Whitney U-test. In graph (C), the performed group comparison is presented with a dotted line, due to a difference close to statistical significance. p < 0.05 was regarded as statistically significant.

The concentration of fasting blood glucose in the LTS+COPD group displayed a strong positive correlation with the neutrophil concentration in blood, FEV1 (% of predicted) and FEV1/FVC ratio, (Figure 2A-C respectively). In contrast, the concentration of fasting glucose displayed a strong negative correlation with the IL-36α concentration in BALF (Figure 2D). In a similar manner, the blood glucose concentration at the end of OGTT in the LTS+COPD group correlated in a negative manner with the concentration of CXCL10 in BALF (Figure 2E). Notably, none of the above correlations were observed in LTS or HNS (Figure S1 in the data supplement). Finally, there were no evident correlations between any of the glucose-related outcomes with BMI, the neutrophil concentration in BAL or with the concentrations of IL-36γ, IL-6, IL-8 and INF-γ in BALF or plasma of LTS+COPD, as applicable (data not shown).

Figure 2 Correlation of fasting blood glucose with (A) neutrophil concentration in blood (n= 5), (B) FEV1 (% of predicted) (n= 6) and (C) FEV1/FVC ratio of LTS+COPD (n= 6). Correlation (D) of fasting glucose with IL-36a in BALF (n= 5) and (E) of blood glucose concentration at the end of OGTT (120 min) with CXCL10 in BALF of LTS+COPD (n= 5).

Abbreviations: FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; LTS+COPD, long-term smokers with COPD; IL-36α, interleukin-36α; BALF, cell-free bronchoalveolar lavage fluid; OGTT, oral glucose tolerance test; CXCL10, C-X-C motif chemokine ligand 10.

Notes: See “Material and methods” regarding the utilized assays. Correlation analyses were performed using Spearman’s rank correlation test. p < 0.05 was regarded as statistically significant.

Neutrophil Concentrations in Long-Term Smokers with COPD

The BAL and blood neutrophil concentrations were higher in LTS+COPD than in HNS (Figure 3A and B). Furthermore, the neutrophil concentration in blood samples, but not in BAL, correlated in a strong and positive manner with FEV1 (% of predicted) (Figure 3C) and in a strong and negative manner with IL-36α concentration in BALF of LTS+COPD (Figure 3D), whereas similar correlations were not observed in either the LTS or the HNS group (Figure S2 in the data supplement). We observed no correlations in the LTS+COPD group for BAL or blood neutrophil concentration, with the concentrations of IL-36γ, IL-6, IL-8, INF-γ or CXCL10 either in BALF or plasma, respectively (data not shown).

Figure 3 Neutrophil concentrations (A) in BAL (n= 5–10) and (B) in blood samples of HNS, LTS and LTS+COPD (n= 5–10). Neutrophil concentration in blood correlated (C) positively with FEV1 (% of predicted) (n= 5) and (D) negatively with IL-36α in BALF of LTS+COPD (n= 5).

Abbreviations: BAL, bronchoalveolar lavage; HNS, healthy non-smokers; LTS, long-term smokers without COPD; LTS+COPD, long-term smokers with COPD; FEV1, forced expiratory volume in 1 second; IL-36α, interleukin-36α; BALF, cell-free bronchoalveolar lavage fluid.

Notes: Data in graphs (A) and (B) are presented as observed and median values. See “Material and methods” regarding the utilized assays for all graphs. In graphs (A) and (B), group comparisons were restricted between the groups of LTS+COPD and HNS, and were performed using the Mann–Whitney U-test. In graphs (C) and (D), the correlation analyses were performed using Spearman’s rank correlation test. p < 0.05 was regarded as statistically significant.

Cytokine Concentrations in Long-Term Smokers with COPD

In a previous publication based on the current study material, we showed that the BALF concentrations of IL-36α and IL-36γ were increased in LTS+COPD compared with HNS.28 In the current study, we found that the BALF IL-36α concentration correlated in a strong and negative manner with FEV1 (% of predicted) in the LTS+COPD group (Figure 4), but not in the LTS or the HNS group (Figure S3 in the data supplement). We did not observe any correlation between IL-36γ and ventilatory lung function. Here, neither IL-36α nor IL-36γ correlated with either of the cytokines IL-6, IL-8 or CXCL10 (data not shown). The LTS+COPD group displayed an increased concentration of IL-8 in BALF compared with the HNS group and this difference was statistically significant (Figure 5A). However, the concentration of CXCL10 in the LTS+COPD group did not differ substantially from the HNS group (Figure 6A). Similarly, we observed no pronounced difference in the concentration of IL-6 in BALF between these groups (Figure S4 in the data supplement). Finally, IL-36β and INF-γ were not detectable in BALF.

Figure 4 Correlation of IL-36α in BALF with FEV1 (% of predicted) in LTS+COPD (n= 5).

Abbreviations: IL-36α, interleukin-36α; BALF, cell-free bronchoalveolar lavage fluid; FEV1, forced expiratory volume in 1 second; LTS+COPD, long-term smokers with COPD.

Notes: See “Material and methods” regarding the utilized assays. Correlation analysis was performed using Spearman’s rank correlation test. p < 0.05 was regarded as statistically significant.

Figure 5 Concentration of IL-8 (A) in cell-free BALF (n= 5–10) and (B) in plasma of HNS, LTS and LTS+COPD (n= 4–10).

Abbreviations: IL-8, interleukin-8; BALF, cell-free bronchoalveolar lavage fluid; HNS, healthy non-smokers; LTS, long-term smokers without COPD; LTS+COPD, long-term smokers with COPD.

Notes: Data are presented as observed and median values. See “Material and methods” regarding the utilized assays. In both graphs, group comparisons were restricted between the groups of LTS+COPD and HNS, and were performed using the Mann–Whitney U-test. p < 0.05 was regarded as statistically significant.

Figure 6 Concentration of CXCL10 (A) in cell-free BALF (n= 5–10) and (B) in plasma of HNS, LTS and LTS+COPD (n= 4–10).

Abbreviations: CXCL10, C-X-C motif chemokine ligand 10; BALF, cell-free bronchoalveolar lavage fluid; HNS, healthy non-smokers; LTS, long-term smokers without COPD; LTS+COPD, long-term smokers with COPD.

Notes: Data are presented as observed and as median values. See “Material and methods” regarding the utilized assays.

The plasma concentration of IL-36α was increased in LTS+COPD compared with HNS, but this was not the case for IL-36γ, as previously demonstrated.28 Neither the concentration of IL-36α nor IL-36γ correlated with the concentrations of IL-6, IL-8 and CXCL10 or with FEV1 (% of predicted) (data not shown). We observed no pronounced group differences in the plasma concentrations of IL-8 (Figure 5B), CXCL10 (Figure 6B), IL-6 and INF-γ (Figure S4 - Data supplement). Just like the case for BALF, IL-36β was not detectable in plasma.

Proteinases in Long-Term Smokers with COPD

The protein concentration of neutrophil elastase in BALF did not differ in a statistically significant manner between the LTS+COPD and the HNS group (Figure 7). This was true as well for net serine proteinase and net gelatinase activity (Figure S5 - Data supplement). Finally, we did not observe any hint of correlations for these proteinases with glucose homeostasis in the group of LTS+COPD (data not shown).

Figure 7 Protein concentration of neutrophil elastase in BALF of HNS, LTS and LTS+COPD (n= 4–10).

Abbreviations: BALF, cell-free bronchoalveolar lavage fluid; HNS, healthy non-smokers; LTS, long-term smokers without COPD; LTS+COPD, long-term smokers with COPD; vs, versus.

Notes: Data are presented as observed and median values. See “Material and methods” regarding the utilized assays. The group comparison between LTS+COPD and HNS was performed using the Mann–Whitney U-test. p < 0.05 was regarded as statistically significant.

Discussion

The results of this pilot study demonstrate that assessments of glucose homeostasis, in terms of fasting blood glucose concentration, change in blood glucose concentration during OGTT and blood glucose concentration at the end of OGTT, differ substantially in long-term smokers with COPD compared to healthy non-smokers. Moreover, these glucose-related outcomes are associated with local and systemic signs of increased neutrophil mobilization in the LTS+COPD group. Collectively, these findings are suggestive of neutrophil mobilization as a unifying pathogenic mechanism associated with alterations of glucose homeostasis in COPD.

In particular, the blood concentration of fasting glucose was markedly decreased in the LTS+COPD group compared with the HNS group, and this decrease was independent of BMI. Notably, this finding is compatible with previous studies showing an accelerated whole-body glycolysis rate in response to increased energy expenditure among patients with COPD.48,49 It is also possible that neutrophils secrete compounds that suppress hepatic glucose production as previously reported in an experimental study in mice and Zucker diabetic fatty rats.50 Along these lines, fasting glucose concentration correlated in a positive manner with FEV1 (% of predicted) and with the FEV1/FVC ratio, in the LTS+COPD group. Thus, our findings are compatible with fasting blood glucose declining as airway obstruction in COPD does progress.2 In addition, we observed that the protein concentration of IL-36α in BALF correlated in a strong and negative manner with fasting glucose and FEV1 (% of predicted) in LTS+COPD; this is interesting given that our previously published data from the same study material demonstrated enhanced concentrations of IL-36α in BALF and blood of this group compared with the HNS group.28 Notably, although IL-36α belongs to the interleukin-1 (IL-1) super family, just like IL-36β and -γ, we failed to detect any correlation between IL-36β and -γ and glucose homeostasis in the current study.29,30 However, to the best of our understanding, this is the first time to describe an association of IL-36α concentration in the airways with fasting blood glucose in smokers with COPD. We interpret this association as a sign that fasting blood glucose decreases in parallel with the progression of local neutrophil mobilization among these patients.

Furthermore, our study showed that the concentration of glucose at the end of OGTT correlated with the concentration of CXCL10 in BALF within the LTS+COPD group, in a strong and negative manner. We find this interesting given that the CXCL10 concentration in BALF was not markedly altered in the LTS+COPD group compared with the HNS group. However, we observed elevated BALF neutrophil concentrations in LTS+COPD compared with HNS, as expected. It is known that neutrophils produce CXCL10, a CXC chemokine, that recruits type 1 T-helper lymphocytes and natural killer cells.35,36,51 Moreover, CXCL10 has previously been related to neutrophil mobilization caused by oxidative stress in an animal airway model and is enhanced in the airways of patients with exacerbation of COPD.37,52,53 Given this and the demonstrated link between CXCL10 and T2DM in a previous publication, we think that our current findings on CXCL10 lend further support to the hypothesis that local neutrophil mobilization in COPD has an impact on glucose homeostasis that may affect the risk of developing T2DM and MetS.38,54

An important observation was that the change in blood glucose concentration during OGTT was more pronounced in the LTS+COPD group than the HNS group. In line with this finding, the LTS+COPD group tended to have a higher concentration of glucose at the end of OGTT than did the HNS group. These findings indicate a trend towards impaired glucose tolerance in COPD, as yet another sign of altered glucose homeostasis in patients with this disease. Moreover, our study showed that the concentration of blood neutrophils in LTS+COPD was increased in comparison with the HNS group and correlated with fasting glucose in a strong and positive manner, which contrasts with our finding of lower fasting glucose in LTS+COPD compared with HNS. Clearly, these seemingly contradictory results motivate further study and evidence for a causative relationship needs to be established. However, this correlation between the blood concentration of neutrophils and fasting glucose indicates that even systemic signs of neutrophil mobilization in COPD are, indeed, associated with altered glucose homeostasis, an alteration that in both of T2DM and MetS can reach pathologic levels.55

The concentration of blood neutrophils correlated with FEV1 (% of predicted) in the LTS+COPD but not in the LTS or the HNS group. Notably, this suggests an association of ventilatory lung function with systemic neutrophil mobilization, due to COPD, rather than with long-term smoking per se. Progressively declining lung function is a common feature of COPD and it has been related in previous studies to the local accumulation of neutrophils in the airways.56 It is of mechanistic interest that this local accumulation is due to the extravasation of systemically circulating neutrophils.16 Given this, our current observation of a positive correlation between blood neutrophil concentration and FEV1 (% of predicted) seems credible, reflecting the increasing tendency of neutrophil transmigration from blood circulation to the airways that follows the impairment of ventilatory lung function as the pathology of COPD progresses. In agreement with the literature, we observed a markedly enhanced concentration of BAL neutrophils in the LTS+COPD in comparison with the HNS group.57 Despite this, we failed to demonstrate statistically significant correlations between BAL neutrophil concentration and lung function in the LTS+COPD group, most likely due to the modest size of our study population.

In addition to our observations of an increased concentration of BAL neutrophils in the LTS+COPD group, we also observed a corresponding enhanced BALF concentration of IL-8 in this study group, reassuring us that our material is representative for COPD. However, the BALF concentration of neutrophil elastase in the LTS+COPD group did not differ in a statistically significant manner from that in the HNS group. Moreover, the net serine proteinase and gelatinase activity did not display any pronounced enhancement in the LTS+COPD group either. Given that neutrophil elastase and other serine proteinases, as well as gelatinases, are released by neutrophils in response to bacterial exposure, we think that these findings reflect the absence of colonization with pathogenic bacteria of the lower airway tract in the LTS+COPD group of the current study population.16 Furthermore, neither neutrophil elastase nor serine proteinase or gelatinase activity in BALF samples correlated with any of the glucose-related outcomes in the LTS+COPD group. This finding suggests that during stable disease, local proteinases are not among the key aspects of neutrophil mobilization that drive the development of metabolic comorbidities of COPD.

Naturally, the modest size of our current study material limited the number of conclusive group comparisons and associations of outcomes. Nevertheless, our careful clinical characterization of subjects and meticulous laboratory investigations enabled the identification of several group differences and correlations that proved statistically significant for outcomes of pathogenic interest, suggesting that the current findings are sound and of noteworthy biological consequence. Most importantly, we ensured stable disease in the LTS+COPD group by addressing signs of exacerbations, infections and change in inflammatory markers. In parallel, we ensured a thorough and reliable characterization of tobacco use in all three study groups, by addressing current and historic tobacco exposure as well as the systemic cotinine concentration. Furthermore, regular treatment with inhaled beta-2-agonists, which is common in patients with COPD, was excluded in this study, not only because of its anti-inflammatory properties, but even due to its potentially confounding effect on glucose homeostasis.58,59 Finally, BMI did not differ markedly in the three study groups and did not correlate with any of our key variables, which indicates that BMI did not act as a confounder in our study and this adds credibility to our findings.

Conclusion

In conclusion, this pilot study forwards the original evidence that altered glucose homeostasis is associated with specific local and systemic signs of neutrophil mobilization in COPD, and this evidence is fully compatible with the increased risk for metabolic comorbidities in this group of patients. Given our novel observations, we postulate that specific aspects of increased neutrophil mobilization constitute a common denominator for type 2 diabetes mellitus/metabolic syndrome and COPD. We think that this new paradigm motivates further mechanistic exploration with more in-depth metabolic phenotyping in larger and dedicated study materials of well-characterized patients with COPD, an exploration that may facilitate the development of novel diagnostic and therapeutic strategies for a large and neglected group of patients.

Acknowledgments

The project funding for this study was provided by the Swedish Heart-Lung Foundation (AL: No. 20210286, SKL: No. 20200579) and King Gustaf V’s and Queen Victoria’s Freemason Research Foundation (AL). Additionally, federal funding was received from Karolinska Institutet (AL), Stockholm Regional Council (ALF: AL: No. 2018-0088) and Västra Götaland Region (LUA: AL: No. 2014-1851). Additional research funding was obtained via Karolinska Severe COPD Center, through unrestricted grants for research infrastructure from AstraZeneca Nordic AB, GlaxoSmithKline AB and Boehringer-Ingelheim AB, Sweden, respectively. The sponsors’ involvement was limited strictly to their financial support, and none played a role in the execution of the study. Finally, the investigators do not have any financial or other binding to the tobacco industry.

The authors express their gratitude to study nurse Monika Crona BSc and biomedical laboratory scientist Dorota Persson BSc, for their crucial contribution in the collection and processing of the study material at Sahlgrenska University Hospital.

Disclosure

Dr Anders Andersson reports personal fees from Novartis, personal fees from Astra-Zeneca, personal fees from Boehringer-Ingelheim, outside the submitted work. Dr Melissa Kovach reports grants from European Respiratory Society, grants from VINNOVA, during the conduct of the study. The authors report no other conflicts of interest for this work.

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Pulmonology devices are used by pulmonologists to treat Respiratory Problems. Pulmonology is a medical specialty that deals with issues concerning the respiratory system. Chest medicine is a medical specialty that treats illnesses including asthma, lung cancer, occupational lung disease, and lung cancer. Pulmonologists use pulmonology instruments to effectively diagnose these diseases and provide adequate care to patients. The increasing occurrence of pulmonary disorders such as acute bronchitis, COPD, lung cancer, asthma, and other associated respiratory disorders is expected to benefit the pulmonology devices industry. Furthermore, the adoption of pulmonology devices with advanced technical and safety features is expected to rise in the industry. Furthermore, increased public understanding of the dangers of lung cancer and the benefits of early detection has resulted in significantly higher acceptance rates. Asthma and COPD patients are more vulnerable to COVID-19 infection, which is expected to drive growth in the pulmonology devices industry.

The latest study released on the Global Pulmonology Device Market by AMA Research evaluates market size, trend, and forecast to 2027. The Pulmonology Device market study covers significant research data and proofs to be a handy resource document for managers, analysts, industry experts and other key people to have ready-to-access and self-analyzed study to help understand market trends, growth drivers, opportunities and upcoming challenges and about the competitors.

Key Players in This Report Include:

Masimo (United States), Boston Scientific Corporation (United States), CONMED Corporation (United States), Olympus Corporation (Japan), Cook Medical Incorporated (United States), Ambu A/S (Denmark), Zydus Cadila (India), Nihon Kohedon Corporation (Japan), Micro-Tech (Nanjing) Co., Ltd (China), Merit Medical Systems (United States)

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Market Trends:

  • Advancement in the Healthcare Devices

Market Drivers:

  • Rising Prevalence of Respiratory Diseases such as lung cancers, asthma, chronic obstructive pulmonary disorders (COPD) and cystic fibrosis
  • Rapid Growth in the Global Geriatric Population

Market Opportunities:

  • Growing Investment in Healthcare Industry

The Global Pulmonology Device Market segments and Market Data Break Down are illuminated below:

by Type (Pulmonary Biopsy Devices (Single- Use Biopsy Forceps, Brushes, Microbiology Brushes), Endobronchial Ultrasound (EBUS) Needles (Biopsy Needles, Transbronchial Aspiration Needles), Airway Stents (Silicon, Nitinol, Stainless Steel), Airway Extraction Baskets, Single-Use Bronchoscopes), Application (Lung Cancer, COPD, Tracheal and Bronchial Stenosis, Others), Distribution Channel (Online, Offline), End-Use (Hospitals, Pulmonology Clinics, Ambulatory Surgical Centers)

Global Pulmonology Device market report highlights information regarding the current and future industry trends, growth patterns, as well as it offers business strategies to helps the stakeholders in making sound decisions that may help to ensure the profit trajectory over the forecast years.

Have a query? Market an enquiry before purchase @ www.advancemarketanalytics.com/enquiry-before-buy/169322-global-pulmonology-device-market

Geographically, the detailed analysis of consumption, revenue, market share, and growth rate of the following regions:

  • The Middle East and Africa(South Africa, Saudi Arabia, UAE, Israel, Egypt, etc.)
  • North America(United States, Mexico & Canada)
  • South America(Brazil, Venezuela, Argentina, Ecuador, Peru, Colombia, etc.)
  • Europe(Turkey, Spain, Turkey, Netherlands Denmark, Belgium, Switzerland, Germany, Russia UK, Italy, France, etc.)
  • Asia-Pacific(Taiwan, Hong Kong, Singapore, Vietnam, China, Malaysia, Japan, Philippines, Korea, Thailand, India, Indonesia, and Australia).

Objectives of the Report

  • -To carefully analyze and forecast the size of the Pulmonology Devicemarket by value and volume.
  • -To estimate the market shares of major segments of the Pulmonology Device
  • -To showcase the development of the Pulmonology Devicemarket in different parts of the world.
  • -To analyze and study micro-markets in terms of their contributions to the Pulmonology Devicemarket, their prospects, and individual growth trends.
  • -To offer precise and useful details about factors affecting the growth of the Pulmonology Device
  • -To provide a meticulous assessment of crucial business strategies used by leading companies operating in the Pulmonology Devicemarket, which include research and development, collaborations, agreements, partnerships, acquisitions, mergers, new developments, and product launches.

Buy Complete Assessment of Pulmonology Device market Now @ www.advancemarketanalytics.com/buy-now?format=1&report=169322

Points Covered in Table of Content of Global Pulmonology Device Market:

Chapter 01 – Pulmonology Device Executive Summary

Chapter 02 – Market Overview

Chapter 03 – Key Success Factors

Chapter 04 – Covid-19 Crisis Analysis on Global Pulmonology Device Market

Chapter 05 – Global Pulmonology Device Market – Pricing Analysis

Chapter 06 – Global Pulmonology Device Market Background

Chapter 07 — Global Pulmonology Device Market Segmentation

Chapter 08 – Key and Emerging Countries Analysis in Global Pulmonology Device Market

Chapter 09 – Global Pulmonology Device Market Structure Analysis

Chapter 10 – Global Pulmonology Device Market Competitive Analysis

Chapter 11 – Assumptions and Acronyms

Chapter 12 – Pulmonology Device Market Research Methodology

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Key questions answered

  • How feasible is Pulmonology Devicemarket for long-term investment?
  • What are influencing factors driving the demand for Pulmonology Devicenear future?
  • What is the impact analysis of various factors in the Global Pulmonology Devicemarket growth?
  • What are the recent trends in the regional market and how successful they are?

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Middle East, Africa, Europe or LATAM, Asia.

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By Dr. Mukesh Batra

The COVID-19 pandemic has tested our medical system in more ways than any of us could’ve imagined. In the past two years, every individual, thanks to the Indian Government, has got a shield against the Novel Coronavirus. Just recently, the Drug Controller General of India (DCGI) approved vaccination for the age group of children between 5 to 12 years. It’s a great initiative to protect children vulnerable to the virus. While some children have suffered short-term health issues, healthy youngsters have shown long-term health hazards driven by Omicron and its new variant BA.2. 

After recovering from the virus, many children have faced health problems for months, one of the side effects of long-COVID or post-COVID. Children have encountered multiple health complications related to weakness, stomach issues, depression, and lungs (like breathing problems, Asthma, pneumonia, lung cancer, chronic mucus, etc.). According to the NCBI, between 0.39–12.3% of children in India were exposed to pandemic-infused respiratory diseases last year, making the virus dangerous for the lungs. Let’s take a brief look at how Long COVID affects kids’ respiratory systems.

Some of the symptoms of long covid can last for 3 months or longer. Children 6 years or older with lasting symptoms may need lung function tests.

How does Long COVID affect the respiratory system?

Although COVID-19 starts with mild flu-like symptoms, it gradually attacks a person’s body and leads to severe symptoms. The virus badly infects the upper or lower portion of the respiratory tract. It travels through the airways, causing the lining to become inflamed and irritated. Some instances show that the infection can even reach the alveoli (tiny air sacs) that transfer oxygen to the blood cells. Such conditions cause symptoms like dry cough, sore throat, heavy breathing, breathing difficulties, increased heart rate, and pneumonia, followed by lung infections where the alveoli get inflamed. As COVID-19 directly correlates with Acute Respiratory Distress Syndrome (ARDS), its adverse effects continue to trouble every individual’s (including kids) respiratory system even after recovering from it. 

With the prevailing health hazards among children, parents desperately opted for various medical systems such as Allopathy, Ayurveda, and Homeopathy, for their kids’ treatment. Fortunately, Homeopathy has garnered significant traction amid the pandemic between the two medical systems, as it is known for treating the root cause of any illness, including respiratory problems. Here’s how homeopathy helps treat respiratory issues in children.

Homeopathy for kids’ immunity

Owing to the safety of the Homeopathic medicines, many mothers prefer them since it ensures great results and proves to be 100% safe for kids. Homeopathy is considered an ideal treatment method for toddlers, infants and young adults. Homeopathic medicines help strengthen a kid’s immunity system and thus, help them fight against flu naturally It has therefore become the preferred medicine system that a lot of countries are starting to adopt.

Homeopathy remedies for respiratory problems

Homeopathic remedies are exceptionally effective in treating respiratory infections without any side effects. Even the National Library of Medicine (NIH) stated the use of homeopathy in fighting respiratory infections and offering symptomatic relief in its clinical trial. Homeopathic medicines provide a practical approach to reducing the symptoms, intensity, and recurrence. Some of the prescribed medicines for respiratory problems include Aconitum Napellas, Hepar Sulphur, Belladonna, Antimonium Tartaricum, and Bryonia alba. But before taking such medications/treatments, consulting your nearest homeopath is always advisable.

Home remedies for respiratory ailments

For respiratory diseases like shortness of breath, deep breathing is exceptionally beneficial for managing breathlessness. Other valuable tips like pursed-lip breathing, steam inhalation, salt water gargling, and consuming fresh ginger & fresh fruits also come to the rescue of kids. In case of severe health conditions, parents must visit the nearest homeopathic medical facility for guidance. 

Apart from respiratory ailments, there are many other side effects of Post COVID-19:

Post-COVID Chronic Cough and Breathlessness: Homeopathy has proven efficacy against respiratory illnesses and provides symptomatic relief. A clinical study published by the National Library of Medicine (NIH) shows its efficacy in combating respiratory infections.

Post-COVID depression: A clinical trial supported the efficacy and safety of homeopathic treatments for depression. The trial concluded that patients who received homeopathic treatments reported lower rates of depression.

Post-COVID gastrointestinal issues: Homeopathy is used to provide relief from a range of gastrointestinal issues. According to Homeopathy360.com, a study conducted on 25 cases of acute diarrhoea observed that 97% of cases were cured, which indicates that homeopathic remedieshave the power to cure the acute diarrhoeal condition.

Post COVID weakness: In 2004, the journal of Psychosomatic Research conducted an extensive triple-blind trial on the effectiveness of individualized homeopathic treatment for chronic fatigue syndrome. This trial was carried out over six months, and results showed that homeopathy treatment had a significant improvement over placebo.

(The author is the Founder, Dr. Batra’s Group of Companies. The article is for informational purposes only. Please consult medical experts and health professionals before starting any therapy, medication and/or remedy. Views expressed are personal and do not reflect the official position or policy of the FinancialExpress.com.)



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Albany NY, United States, May 17, 2022 (GLOBE NEWSWIRE) -- The global mechanical ventilators market is estimated to register growth at a CAGR of 12.8% during the forecast period 2019 to 2027, as per a research report by Transparency Market Research (TMR).

With rising focus of government authorities of many developed and developing nations across the globe, there has been increase in the number of hospital beds in these nations. Moreover, the number of critically ill patients around the world has been increased in the recent years. These factors are generating significant business prospects in the market for mechanical ventilators. This aside, the mechanical ventilators market is estimated to be driven by rising focus of major hospitals on providing excellent level of patient care.

Rise in the spread of COVID-19 globally has resulted into increase in the need for intensive care for the patients dealing with this condition. Hence, government authorities of many nations have increased the demand for mechanical ventilators. This factor, in turn, is bolstering the growth of the global mechanical ventilators market. Thus, the global mechanical ventilators market is prognosticated to be valued at US$ 5.5 Bn by 2027.

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The mechanical ventilators market in North America is estimated to gain sizable growth prospects owing to several factors such as increase in the R&D projects by regional companies and early adoption of advanced medical device technologies in the regional healthcare sector. Moreover, the presence of sturdy healthcare infrastructure is prognosticated to help in the growth of the North America mechanical ventilators market in the years ahead.

Several companies operating in the global mechanical ventilators market are focusing on conducting R&Ds, launching new products, and regulatory approvals. In addition, market players are also utilizing strategies such as collaborations and partnerships in order to stay ahead of the competition. Moreover, many companies operating in the global mechanical ventilators market are concentrating on the development of technologically advanced products. These efforts are estimated to help in the expansion of the global market for mechanical ventilators.

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Mechanical Ventilators Market: Key Findings

  • In the recent years, there has been a surge in the prevalence of different chronic respiratory diseases including asthma, chronic obstructive lung disease, such as bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, neoplasms of respiratory and intrathoracic pulmonary heart disease, lung cancer, and diseases pertaining to the pulmonary circulation. Hence, rise in different respiratory disorders is leading into increase the demand opportunities in the global mechanical ventilators market.
  • The World Health Organization (WHO) notes that approximately 65 million population deal with COPD and 3 million expire due such health conditions every year. Hence, COPD is considered the third-leading reason for death globally. This factor is driving the demand for mechanical ventilators, notes a TMR study on the global mechanical ventilators market.

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Mechanical Ventilators Market: Growth Boosters

  • Increase in the older population and surge in the cases of respiratory diseases globally are boosting the sales growth in the mechanical ventilators market
  • Rise in number of patients dealing with COPD and acute respiratory distress syndrome (ARDS) is expected to boost the demand opportunities in the market

Mechanical Ventilators Market: Key Players

Some of the key players profiled in the report are:

  • VYAIRE
  • Teleflex Incorporated
  • GE Healthcare
  • Dragerwerk AG & Co. KGaA
  • Koninklijke Philips N.V.
  • Medtronic plc
  • ResMed Inc.
  • Smiths Medical
  • Getinge AB.
  • Bunnell Inc.

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Mechanical Ventilators Market Segmentation

Product

  • Critical Care Ventilators
  • Neonatal Ventilators
  • Transport and Portable Ventilators

Interface

End-user

  • Home Care
  • Hospitals and Clinics
  • Ambulatory Surgical Centers
  • Others

Region

  • North America
  • Europe
  • Asia Pacific
  • Latin America
  • Middle East & Africa

Modernization of healthcare in terms of both infrastructure and services have pushed the healthcare industry to new heights, Stay Updated with Latest Healthcare Industry Research Reports by Transparency Market Research:

Non invasive Ventilators Market: Technical advancements in non-invasive ventilators have augmented the accuracy and reliability of these systems for the diagnosis of respiratory diseases. Moreover, their extensive applications in diagnosing others diseases is likely to fuel the non-invasive ventilators market.

Portable Ventilators Market: Rise in hospital admissions owing to increase in incidence of COPD and surge in emphasis on home care are projected to drive the global portable ventilators market. Presently, usage of portable ventilators has increased due to the outbreak of Covid-19 across the world.

Veterinary Ventilators Market: The high prevalence of respiratory disease among veterinary animals, rising veterinary animal disease awareness programs, growing research and development initiatives, growing demand for veterinary ventilators devices as it is easy-to-use and controls to make operations simple makes the devices most important driving factor for veterinary ventilators market.

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This article was originally published here

Prog Rehabil Med. 2022 Apr 29;7:20220022. doi: 10.2490/prm.20220022. eCollection 2022.

ABSTRACT

BACKGROUND: Advances in cancer treatment have led to an increase in the number of cancer survivors and, likewise, cancer patients in convalescent rehabilitation wards. It is difficult for patients with bone metastases to recover their motor functions and be discharged. However, cancer treatments, such as anti-cancer drug therapy and radiation therapy, are not generally provided in convalescent rehabilitation wards.

CASES: This study retrospectively reviewed six cases of bone metastases in our convalescent rehabilitation ward from April 2018 to October 2019. The ages of the patients ranged from 58 to 85 years, and all patients were male. The primary cancers were lung cancer (two cases), renal cancer (one case), esophageal cancer (one case), prostate cancer (one case), and double lung and kidney cancer (one case). Bone metastases were observed in the spine (six cases), pelvis (two cases), and femur (one case). All patients were admitted to our convalescent rehabilitation ward for postoperative management of imminent fracture risk and rehabilitation of pathological fracture or spinal cord compression caused by bone metastasis. None of the patients received treatment for primary cancer or bone metastases during their hospitalization. Two patients had new bone metastases in load-bearing bones. Five patients were transferred to acute care hospitals for the treatment of cancer or infection.

DISCUSSION: Before transferring patients with bone metastases to convalescent rehabilitation wards, clinicians should assess the risk of skeletal-related events and the rate of progression of their cancer. Indications for hospitalization should be carefully determined in cooperation with acute care hospitals.

PMID:35573804 | PMC:PMC9043833 | DOI:10.2490/prm.20220022



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Major players in the respiratory devices and equipment (therapeutic) market are Hamilton Medical AG, Koninklijke Philips N. V, Smiths Medica, Ge Healthcare, Philips Health Care, Chart Industries, Invacare Corporation, Fisher & Paykel Healthcare Limited, Resmed, and Dragerwerk AG.

New York, May 16, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Respiratory Devices And Equipment (Therapeutic) Global Market Report 2022" - www.reportlinker.com/p06277169/?utm_source=GNW

The global respiratory devices and equipment (therapeutic) market is expected to grow from $16.33 billion in 2021 to $18.03 billion in 2022 at a compound annual growth rate (CAGR) of 10.4%. The market is expected to grow to $26.83 billion in 2026 at a compound annual growth rate (CAGR) of 10.4%.

The respiratory devices and equipment (therapeutic) market consists of sales of respiratory devices and equipment used to treat patients with acute or chronic respiratory disorders such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, sleep disorders, etc.

The main products of the respiratory devices and equipment (therapeutic) market are nebulizers, humidifiers, oxygen concentrators, positive airway pressure devices, ventilators, capnographs, and gas analyzers.A nebulizer is a small machine that turns liquid medicine into a mist, sits with the machine, and breathes in by a connected mouthpiece.

The various technologies involved in the respiratory devices and equipment are HEPA filter, electrostatic filtration, microsphere separation, hollow fiber filtration, and others. The market covered in this report is segmented by end-users into home care settings and hospitals.

Asia Pacific was the largest region in the respiratory devices and equipment (therapeutic) market in 2021.Western Europe was the second-largest region in the respiratory devices and equipment (therapeutic) market.

The regions covered in this report are Asia-Pacific, Western Europe, Eastern Europe, North America, South America, Middle East, and Africa.

The market for respiratory devices and equipment is expected to expand rapidly.The fact that COVID-19 is essentially a respiratory ailment has boosted the use of respiratory monitoring devices, in turn contributing to the growth of this market.

Currently, there is a huge demand for respiratory devices including ventilators, especially in developing countries. Companies across the globe are focusing on increasing the availability of ventilators, nebulizers, and other respiratory support devices for patients.

The rising prevalence of respiratory diseases such as Chronic Obstructive Pulmonary Disorder (COPD) and sleep apnea contributed to the growth of the therapeutic respiratory devices and equipment market. According to World Health Organization, one million people die due to chronic obstructive pulmonary diseases caused by smoking among the 4.9 million people who die due to tobacco consumption and 65 million people suffer from moderate to severe COPD. As per its estimates, COPD is predicted to be the third leading cause of death worldwide and potentially fatal respiratory diseases. Tuberculosis, COPD, and lung cancer will account for about one in five deaths worldwide by 2030. According to National Health Interview Survey by the Centers for Disease Control and Prevention (CDC), the number of adults with diagnosed chronic bronchitis in the USA was 9.0 million. In the USA, it is estimated that 22 million Americans suffer from sleep apnea, with 80% of the cases of moderate and severe obstructive sleep apnea undiagnosed. According to epidemiological studies presented at the Associated Professional Sleep Societies in 2019, 37% of adults in North, Central, and South America suffer from Obstructive sleep apnea (OSA). The increased prevalence of COPD and sleep apnea in the geriatric population is driving the market for therapeutic respiratory devices.

Lack of awareness regarding the usage of respiratory devices has always been a major challenge in the therapeutic respiratory device market.Outcomes for patients with chronic respiratory diseases remain poor despite the development of novel therapies.

An International Survey conducted on Noninvasive Ventilation Use for Acute Respiratory Failure in General Non-Monitored Wards in 51 countries from 5 continents revealed that 44% of the GPs and physicians reported that they had never performed spirometry to make a diagnosis of COPD and the NIV application in general wards was reported by only 66% of respondents.Limited training and human resources were the most common reasons for not using NIV in general wards.

The lack of awareness on the use of respiration devices is negatively affecting the respiratory devices and therapeutics market.

The companies in the respiratory devices and equipment therapeutic market are increasingly using AI to develop respiratory devices to treat Asthma and COPD.Artificial intelligence supports the development of innovative sensors-equipped inhalers which help patients to track their dosage intake.

These sensors are durable and consume less power and help caution the patients by noting the differences or fluctuations in respiration.These are used for both add-on and embedded inhalers.

These inhalers with sensors can track data automatically and can alert both the doctors and patients about the health condition of the patients.Also, the companies in developing devices such as AI aided imaging systems and AI aided platforms that will act as voice biomarkers.

For instance, Verbal and Healthymize, two early-stage Israeli AI health tech companies, announced a merger in 2019 to create a joint company (Vocalis Health) that will be a global leader in vocal biomarkers which develops an artificial intelligence-based platform that uses voice interaction through a call center or smart device to passively screen and monitor millions of patients that live with a range of voice-affecting diseases, like chronic respiratory or cardiac conditions or depression.

In March 2020, Masimo, a global leader in noninvasive monitoring technologies acquired NantHealth, Inc’s connected care business for an undisclosed amount.NantHealth is a provider a tablet-optimized application that sits on top of our DCX platform to provide clinicians more convenient and ubiquitous access to capture a wide array of patient vitals such as respiratory rate, blood pressure, and heart rate in addition to performing patient assessments.

This move of Masimo will leverage its capabilities with NantHealth’s solutions that can enable a more efficient patient rounding and assessment workflow by providing a near real-time stream of data from the patient’s bedside unlike periodic sampling typically entered into an EHR hours later.

The countries covered in the respiratory devices and equipment (therapeutic) market are Australia, Brazil, China, France, Germany, India, Indonesia, Japan, Russia, South Korea, UK, and USA.
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Introduction

Chronic obstructive pulmonary disease (COPD) is a clinical syndrome that features chronic respiratory symptoms and structural pulmonary abnormalities leading to lung function impairment with persistent airflow limitation.1 A recent study indicated that the overall prevalence of spirometry defined for COPD was 8.6% of adults in China, including 11.9% of men aged 40 years or older. The acute exacerbation of COPD (AECOPD) is a key factor that affects the disease prognosis and leads to hospitalization. Thus, AECOPD-related morbidity and mortality should be given more attention.2,3 Pulmonary hypertension (PH) is a common and severe comorbidity of COPD that results in an increased risk of hospitalization, reduced exercise capacity, and shorter survival. Right-heart catheterization (RHC) is the “gold standard” for the diagnosis of PH. However, RHC related significant risks and its difficulty of placement limits this procedure in patients with PH. Echocardiography is a noninvasive method that is widely used to assess PH in patients with AECOPD.4 A tricuspid regurgitant jet ≥3 m/s tested by echocardiography is diagnosed as PH, which may lead to underdetermined diagnoses of PH.5 Moreover, pulmonary artery systolic pressure detected by echocardiography is poorly correlated with the mean pulmonary artery pressure (mPAP) in severe COPD. A main pulmonary artery to ascending aorta diameter ratio (PA/A) of greater than one has been reported to be a promising indicator for revealing PH.6,7 Furthermore, an increased ratio of PA/A was closely associated with the poor survival of patients with COPD, particularly in individuals with moderate-to-severe cases.8 Nevertheless, the impact of the PA/A ratio in AECOPD remains to be elucidated. In this present study, we aim to disclose the associations between the PA/A ratio and clinical outcomes in hospitalized patients with AECOPD.

Patients and Methods

Study Population

This retrospective observational study was conducted at the Yijishan Hospital affiliated with the Wannan Medical College and was approved by the Research Ethics Committee of Yijishan Hospital. The clinical data of patients was maintained with confidentiality and in compliance with the Declaration of Helsinki. Written informed consent from patients was waived due to the retrospective nature of this study. Consecutive AECOPD patients admitted to the Department of Respiratory Medicine and Respiratory Intensive Care Units (RICU) were reviewed from September 2017 to July 2021. Patients with advanced lung cancer, pneumothorax, stroke, pneumonia, diffuse interstitial lung disease, hemodialysis, or left-heart failure, as well as those who only accepted palliative therapy, or had a lack of chest computed tomography (CT) images, were excluded from the final analysis.

AECOPD is defined as COPD with an acute worsening of respiratory symptoms (typically cough, dyspnea, increased sputum volume, and/or sputum purulence) requiring additional treatments.9 Indications for RICU admission were made according to the expert consensus released in 2014 on AECOPD in China.10 In brief, these consisted of a significant increase in symptom intensity (severe dyspnea, changes in mental status, moderate or severe hypoxemia with or without hypercapnia), failure of an exacerbation to respond to initial medical management, hemodynamic instability, and a patient requiring mechanical ventilation (MV). The treatment success of AECOPD patients was defined as improvement in the clinical condition when discharged from the hospital. Conversely, treatment failure was thought to occur as an event of in-hospital death or deterioration of the clinical condition prior to discharge.

Demographic characteristics, including gender, age, the age-adjusted Charlson Comorbidity Index (aCCI), length of stay, body mass index (BMI) and in-hospital death, were collected. Laboratory tests, including an arterial blood gas analysis (pH value, oxygenation index, the ratio of arterial partial pressure of oxygen to the fraction of inspired oxygen), PaCO2, and the blood lactate level), hemoglobin, blood red cell distribution width (RDW), D-dimer, brain natriuretic peptide (BNP), fibrinogen (Fib), and blood platelet (PLT), were initially recorded after admission. The percentage of ICU admissions requiring invasive MV (IMV) was also calculated. A chest CT was performed when the patient was admitted to the hospital. The procedure for measuring the pulmonary artery (PA) diameter and PA/A ratio determined by the chest CT conformed to a previous study.6 Briefly, the PA diameter and ascending aorta diameter were averaged from two perpendicular measurements at the PA bifurcation level collected from the same chest CT images, as shown in Figure 1.

Figure 1 Diameters of the PA and A were determined by CT scan at the PA bifurcation. (A) PA/A ratio < 1; (B) PA/A ratio > 1.

Abbreviations: A, aorta; PA, pulmonary artery.

Statistical Analysis

Continuous data were analyzed using a normal distribution test prior to further analysis. Continuous data are indicated as the mean (standard deviation [SD]) or median (inter-quartile range [25,75]). Categorical variables are presented as the number (n) or percentage. Continuous variables were analyzed using the independent t-test or the Mann-Whitney U-test, and categorical variables were analyzed using a Chi-square test. The logistic regression model was used as a multivariate analysis to reveal the independent risk factors of in-hospital worst outcomes in patients with AECOPD. The Kaplan–Meier survival method was used to analyze the effect of the PA/A ratio on outcomes of AECOPD patients. A Log rank test was applied to appraise the statistical differences between the two survival curves. A receiver operating characteristic (ROC) curve analysis was conducted to evaluate factors predicting an in-hospital worst outcome. A P value less than 0.05 was considered statistically significant. The statistical analyses were performed using SPSS for Windows (release 22.0, IBM Corporation, USA).

Results

As indicated in Figure 2, a total of 229 patients with AECOPD were reviewed. According to the inclusion criteria and exclusion criteria, 111 patients were excluded due to the condition being combined with advanced lung cancer (n = 10), pneumothorax (n = 4) stroke (n = 5), pneumonia (n = 29), diffuse interstitial lung disease (n = 7), hemodialysis (n = 6), left-heart failure (n = 19), palliative therapy (n = 23), and a lack of CT images (n = 10). Ultimately, 118 eligible individuals were reviewed in this study: 74 individuals with a PA/A ratio <1 and 44 individuals with PA/A ratio ≥1. The outcomes of 21 patients were treatment failures, and 97 patients were treatment successes when discharged from the hospital.

Figure 2 A flowchart of this study.

Characteristics of the AECOPD Patients with a PA/A Ratio <1 or a PA/A Ratio ≥1

The pH value in the PA/A ratio ≥1 group was significantly lower than that in the PA/A ratio <1 group (p = 0.026). Remarkably, the PA/A ratio ≥1 group had a significantly higher value of PaCO2, RDW, BNP, PA diameter, and RICU admissions, as well as worse outcomes than the PA/A ratio <1 group (P < 0.05). However, there were no significant statistical differences for the other indicators between the two groups (Table 1).

Table 1 Characteristics of AECOPD Patients with Different PA/A Ratio

Clinical Features of the AECOPD Patients with Treatment Failure

As indicated in Table 2, compared to the treatment success group, the treatment failure group had a much lower pH value (7.34 ± 0.11 vs 7.28 ± 0.13, respectively, p = 0.040) and less count of PLT (median 167 × 109/L vs 130 × 109/L, respectively, p = 0.018). The treatment failure group had higher levels of D-dimer and BNP compared with the improved group (P < 0.05). In addition, the percentage of RDW, rate of RICU admissions, and the proportion of IMV in the treatment failure group were significantly higher than that in the improved group (P < 0.05). Notably, the PA diameter and PA/A ratio were significantly increased in the treatment failure group than in the improved group (mean PA diameter: 3.71 vs 3.22, p = 0.001; mean PA/A ratio: 1.09 vs 0.89, p < 0.001).

Table 2 Characteristics of Treatment Success Group and Treatment Failure Group in Severe AECOPD

A PA/A Ratio ≥1 Was an Independent Risk Factor for Treatment Failure in AECOPD

The multivariate analysis indicated that the PA/A ratio ≥1 (OR value = 6.129, 95% CI: 1.665–22.565, p = 0.006) and IMV (OR value = 10.798, 95% CI: 2.072–56.261, p = 0.005) were two independent risk factors for treatment failure in patients with AECOPD. Although the RDW, D-dimer, PLT, and RICU admissions had observed significant differences between the two groups according to the univariate analysis, they did not reach significant statistical differences according to the multivariate analysis (Table 3). Additionally, the Kaplan–Meier survival analysis indicated that patients with a PA/A ratio ≥1 had worse outcomes than patients with a PA/A ratio <1 during hospitalization (HR = 5.277, 95% CI: 2.178–12.78, p < 0.001) (Figure 3).

Table 3 Multivariate Analysis for Risk Factors of Treatment Failure in AECOPD

Figure 3 Effect of the PA/A ratio on the outcomes of AECOPD patients.

Abbreviation: PA/A ratio: main pulmonary artery to ascending aorta diameter ratio.

Note: A Kaplan–Meier survival curve analysis was performed, and a Log rank test was used, and a P < 0.05 was considered statistically significant.

Predictors of Treatment Failure in Hospitalized Patients with AECOPD

Figure 4 displays the diverse ROC curve of the PA/A ratio, the PA value, the BNP, and the RDW for predicting treatment failure in hospitalized patients with AECOPD. Even though there were no significant statistical differences observed, the area under the curve (AUC) value of the PA/A ratio was numerically larger than that of the other indicators. The best cut-off value of the PA/A ratio for predicting treatment failure was 0.925. The sensitivity was 81.82%, and the specificity was 66.67% (Table 4).

Table 4 ROC Curve Analysis for Factors Predicting Treatment Failure

Figure 4 PA/A ratio, PA value, BNP, and RDW for predicting treatment failure in hospitalized patients with AECOPD.

Abbreviations: PA/A ratio, main pulmonary artery to ascending aorta diameter ratio; PA, main pulmonary artery; RDW, blood red cell distribution width; BNP, brain natriuretic peptide.

Note: The receiver operating characteristic (ROC) curve analysis was conducted to evaluate factors predicting in-hospital worst outcomes.

Discussion

The strengths of this study were its primary findings. First, patients with a PA/A ratio ≥1 had significantly higher PaCO2, RDW, BNP, PA diameters, RICU admission rates, and proportions of treatment failure. Second, the PA diameter and PA/A ratio were significantly increased in the treatment failure group compared with the treatment success group. Third, a PA/A ratio ≥1 was an independent risk factor for treatment failure in patients with AECOPD. The Kaplan–Meier survival analysis indicated that patients with a PA/A ratio ≥1 had worse outcomes than patients with a PA/A ratio <1 during hospitalization. Finally, the PA/A ratio may be a promising factor for predicting treatment failure in hospitalized AECOPD patients.

A previous study indicated that the relative pulmonary arterial enlargement (PA/A ratio >1 on CT scanning) predicted hospitalization for AECOPD, and a PA/A ratio >1 with increased blood troponin levels shared close associations with increased respiratory failure, ICU admission, and in-hospital mortality.11 Iliaz et al reported that the PA/A ratio was related to the frequency of hospitalizations and exacerbations due to COPD in one year after hospital discharge.12 However, the relationships between a PA/A ratio >1 alone and ICU admission or in-hospital mortality are still unclear. In the present study, we found that AECOPD patients with a PA/A ratio ≥1 had a decreased pH value and increased PaCO2 compared with patients with a PA/A ratio <1, implicating increased type II respiratory failure in patients with a PA/A ratio ≥1. A decreased pH value and increased PaCO2 may contribute directly to pulmonary vasoconstriction leading to a rise in pulmonary vascular resistance and pulmonary arterial pressure.13 In addition, we also disclosed a higher percentage of RICU admissions and a markedly increased rate of treatment failure in hospitalized AECOPD patients with a PA/A ratio ≥1. Thus, an increased PA/A ratio was associated with severity and worse outcomes in inpatients with AECOPD. Many studies have revealed that the RDW is a valuable biomarker for predicting pulmonary hypertension and its associated prognosis.14–16 In a previous study performed by our group, we indicated that the RDW shared positive relationships with the PA/A ratio in patients with pH secondary to COPD.17 Similar to previous studies, we found an increase in the RDW in AECOPD patients with a PA/A ratio ≥1. Likewise, the serum level of BNP was drastically elevated. BNP is an important indicator for identifying risk categories in PH. Increased BNP is related to a worse outcome of PH.18

In this study, we demonstrated that there was a decreased pH value, lower number of PLTs, and increases in the RDW, D-dimer, BNP, PA diameter, and PA/A ratio in AECOPD patients with treatment failure compared with the improved group. Patients with treatment failure also required more IMV supports and intensive care. It was reported that lower pH values were associated with short or long mortality in hospitalized AECOPD patients.19,20 RDW is an indicator that reflects the heterogeneity of red blood cell volume. Recently, RDW was found to be an independent negative prognostic factor closely associated with adverse outcomes in hospitalized AECOPD patients.21,22 Dysregulation of erythrocyte homeostasis and metabolic imbalance may account for significant changes in the RDW in AECOPD patients. However, the underlying pathophysiological mechanisms remain unknown.23 A hypercoagulable state is a feature of hospitalized AECOPD patients. An increased D-dimer level is not only an important independent risk factor for pulmonary embolism in inpatients with AECOPD but also a predictor of higher mortality in stable COPD patients.24,25 Cardiac failure is a frequent complication of AECOPD, deeply affecting exercise tolerance and life span in patients with COPD. BNP is widely used to evaluate heart function. BNP can be used to risk-stratify, and an elevated BNP is associated with a higher MV use and worse outcomes in AECOPD patients.26 An increased PA/A ratio is positively correlated with COPD severity. Previous studies have reported that pulmonary artery enlargement detected by CT is a risk predictor for a severe exacerbation of COPD.27,28 Intriguingly, the PA/A ratio is an important determinant of mortality in moderate-to-severe COPD.8 In our present study, we found that a PA/A ratio ≥1 was a strong independent risk-factor of in-hospital treatment failure in patients with AECOPD. In addition, the PA/A ratio might be a better predictor of in-hospital treatment failure compared with other indicators including the PA value, BNP, and RDW. Taken together, the results of the present study provide additional evidence for a close association between the PA/A ratio and the outcome of AECOPD.

In this study, AECOPD patients with a PA/A ratio ≥1 had markedly higher values of PaCO2, RDW, BNP, the PA diameter, ICU admission rates, and proportions of treatment failure and had worse outcomes during hospitalization. A PA/A ratio ≥1 was an independent risk factor for treatment failure in patients with AECOPD. The PA/A ratio may be a promising predictor for treatment failure. It is worth noting that there are several limitations in this study. First, the sample size was small, and this might lead to an interpretation bias in the final analysis. Further work is required to validate the initial conclusion for a larger sample size. Second, the PA/A ratio partially reflects a change in the pulmonary artery pressure. However, the association between the PA/A ratio and the pulmonary artery pressure was not assessed in this study. Finally, to reduce the chance of radioactive exposure, a dynamic change in the PA/A ratio during hospitalization was unclear.

Acknowledgments

We thank LetPub for its linguistic assistance during the preparation of this manuscript.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The design of the study and collection, analysis, and interpretation of data were supported by the Anhui Provincial Key projects of the Natural Science Foundation for Colleges and Universities (KJ2021A0834).

Disclosure

The authors report no conflicts of interest in this work.

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18. Hoeper MM, Pausch C, Olsson KM, et al. COMPERA 2.0: a refined 4-strata risk assessment model for pulmonary arterial hypertension. Eur Respir J. 2021;2102311. doi: 10.1183/13993003.02311-2021

19. Gayaf M, Karadeniz G, Guldaval F, et al. Which one is superior in predicting 30 and 90 days mortality after COPD exacerbation: DECAF, CURB-65, PSI, BAP-65, PLR, NLR. Expert Rev Respir Med. 2021;15:845–851. doi:10.1080/17476348.2021.1901584

20. Chen L, Chen L, Zheng H, et al. Emergency admission parameters for predicting in-hospital mortality in patients with acute exacerbations of chronic obstructive pulmonary disease with hypercapnic respiratory failure. BMC Pulm Med. 2021;21:258. doi:10.1186/s12890-021-01624-1

21. Hu GP, Zhou YM, Wu ZL, et al. Red blood cell distribution width is an independent predictor of mortality for an acute exacerbation of COPD. Int J Tuberc Lung Dis. 2019;23:817–823. doi:10.5588/ijtld.18.0429

22. Epstein D, Nasser R, Mashiach T, et al. Increased red cell distribution width: a novel predictor of adverse outcome in patients hospitalized due to acute exacerbation of chronic obstructive pulmonary disease. Respir Med. 2018;136:1–7. doi:10.1016/j.rmed.2018.01.011

23. Salvagno GL, Sanchis-Gomar F, Picanza A, et al. Red blood cell distribution width: a simple parameter with multiple clinical applications. Crit Rev Clin Lab Sci. 2015;52:86–105. doi:10.3109/10408363.2014.992064

24. Wang J, Ym D. Prevalence and risk factors of pulmonary embolism in acute exacerbation of chronic obstructive pulmonary disease and its impact on outcomes: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2021;25:2604–2616. doi:10.26355/eurrev_202103_25424

25. Husebo GR, Gabazza EC, D’Alessandro GC, et al. Coagulation markers as predictors for clinical events in COPD. Respirology. 2021;26:342–351. doi:10.1111/resp.13971

26. Vallabhajosyula S, Haddad TM, Sundaragiri PR, et al. Role of B-type natriuretic peptide in predicting in-hospital outcomes in acute exacerbation of chronic obstructive pulmonary disease with preserved left ventricular function: a 5-year retrospective analysis. J Intensive Care Med. 2018;33:635–644. doi:10.1177/0885066616682232

27. Yang T, Chen C, Chen Z. The CT pulmonary vascular parameters and disease severity in COPD patients on acute exacerbation: a correlation analysis. BMC Pulm Med. 2021;21:34. doi:10.1186/s12890-020-01374-6

28. Wells JM, Washko GR, Han MK, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med. 2012;367:913–921. doi:10.1056/NEJMoa1203830

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MADISON, Wis. – The U.S. Environmental Protection Agency (EPA) is accepting public comments on its federal clean trucks rule until Monday May 16. Ahead of the deadline, Wisconsin Environment, Wisconsin Health Professionals for Climate Action, and Masters Gallery Foods presented a webinar on Thursday, Clean Trucks for Wisconsin, that highlighted the benefits of cleaner trucks for the state. Heavy-duty vehicles, including trucks and buses, emit toxic air pollutants that cause and exacerbate heart and respiratory diseases from asthma to lung cancer. Those vehicles also emit greenhouse gases that contribute to the climate crisis.

“Cleaning up the pollution from the biggest trucks on our roads is necessary to slow global warming,” said Wisconsin Environment Destination: Zero Carbon director Morgan Folger. “From life-threatening heat waves to severe storms and flooding, we’re already seeing devastating impacts of climate change in Wisconsin. To protect our lungs and our climate, EPA needs to strengthen this rule.”

At the webinar, the panelists discussed the threats of toxic diesel pollution from trucks and buses, and how strong action from the EPA could deliver cleaner air and accelerate the transition to electric trucks. Speakers included:

  • Dr. Victoria Gillet, member of Wisconsin Health Professionals for Climate Action

  • Eric Jens, Director of Supply Chain – Logistics/Warehouse, Masters Gallery Foods

  • Morgan Folger, Destination: Zero Carbon director, Wisconsin Environment

Transportation is the second-largest contributor to climate change in Wisconsin, fueling the extreme weather that has devastated families, farms and businesses across the state. Transportation-related pollution may also have disproportionately larger impacts on health compared to other sources because they generally emit pollution closer to people.

“Pollution from diesel-powered trucks and buses pollutes our air with nitrogen oxide emissions, ground-level ozone and particle pollution,” said Milwaukee-based internal medicine specialist Dr. Victoria Gillet. “From the moment of conception to their last breath, exposure to these pollutants makes my patients sicker causing still births, preterm births, delayed cognitive development in children, asthma, heart attacks, cancer, strokes, and dementia. It is not right that breathing air can make you so sick.”

The EPA’s proposed clean trucks rule would limit smog-forming nitrogen oxides (NOx) and create a greenhouse gas emission standard for trucks. Advocates called on the agency to strengthen the rule to push the truck manufacturing industry to reduce pollution and accelerate the market for electric trucks. In addition to the health and climate benefits associated with zero tailpipe pollution, electric trucks provide an opportunity for businesses to save money on fuel and maintenance while reducing their environmental impact.

“Masters Gallery Foods strives to manufacture and distribute products with minimum energy consumption and waste generation,” said Andy Pfister, vice president of procurement and industrial sales for Masters Gallery Foods. “The Orange EV truck aligns with our sustainability efforts, providing a significant increase in efficiency and longevity compared to diesels, thereby also reducing the necessity and frequency of replacing vehicles. Our plan is to go completely electric with our terminal fleet by June 2023.”

With federal climate action uncertain in congress, the Biden Administration must focus on executive agency actions to tackle the climate crisis. EPA’s clean trucks rule can help meet President Joe Biden’s goal of reaching 50% emissions reductions by 2030. Members of the public can submit comments to the EPA until Monday, May 16.

“Cleaner trucks can deliver cleaner air for Wisconsin,” concluded Folger. “The EPA should go back to the drawing board to create a rule that will safeguard our health and climate.”

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Major players in the respiratory devices and equipment market are Smiths Medical, Philips Healthcare, GE Healthcare, Chart Industries, Invacare Corporation, Fisher & Paykel Healthcare Limited, ResMed, Dragerwerk AG, Medtronic plc, Masimo corp.

New York, May 13, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Respiratory Devices And Equipment (Therapeutic And Diagnostic) Global Market Report 2022" - www.reportlinker.com/p06277193/?utm_source=GNW
, and CareFusion Corporation.

The global respiratory devices and equipment (therapeutic and diagnostic) market is expected to grow from $25.23 billion in 2021 to $28.97 billion in 2022 at a compound annual growth rate (CAGR) of 14.8%. The market is expected to grow to $47.86 billion in 2026 at a compound annual growth rate (CAGR) of 13.4%.

The respiratory devices and equipment (therapeutic and diagnostic) market consist of sales of respiratory devices and equipment (therapeutic and diagnostic) and related services. Respiratory devices and equipment are used to provide medication or assist a patient who is having difficulty in breathing and cannot achieve adequate oxygen levels to maintain life.

The main types of respiratory devices and equipment are diagnostic devices, therapeutic devices, and monitoring devices.The diagnostic devices are used to diagnose respiratory-related issues.

The various therapeutic devices are humidifiers, nebulizers, oxygen concentrators, positive airway pressure (PAP) devices, ventilators, and others.The diagnostic devices involved are spirometer, polysomnographs, and peak flow meters and monitoring devices are pulse oximeters, capnography, and gas analyzers.

These provide applications in chronic obstructive pulmonary disease (COPD), asthma, obstructive sleep apnea (OSA), respiratory distress syndrome (RDS), cystic fibrosis, and pneumonia. These are used by hospitals, clinics, home care settings, and ambulatory service centers.

Asia Pacific was the largest region in respiratory devices and equipment (therapeutic and diagnostic) market in 2021.Western Europe was the second-largest region in respiratory devices and equipment (therapeutic and diagnostic) market.

The regions covered in this report are Asia-Pacific, Western Europe, Eastern Europe, North America, South America, Middle East, and Africa.

The global therapeutic respiratory devices and equipment market will be driven by the increase in diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma, and lung cancer.Growth in the geriatric population, tobacco consumption, allergens, and air pollutants increase the prevalence of respiratory diseases, in turn driving the global therapeutic respiratory devices market.

According to World Health Organisation,4.9 million people die due to tobacco consumption, and smoking causes chronic obstructive pulmonary diseases (1 million deaths annually), cardiovascular and respiratory diseases (1.7 million deaths annually), and lung cancer (0.85 million deaths annually). According to an Italian journal, COPD in the U.S. is estimated to be 10% in the population aged 75 years or over. According to Asthma UK, 5.4 million people in the UK are currently receiving treatment for asthma out of these 1.1 million are children and 4.3 million are adults.

A longer duration of time taken in the approval process of the respiratory devices is restricting the respiratory devices and equipment market growth. Before a new respiratory device is introduced to the market, it takes 7.2 months for the FDA approval process, which adds to development costs to be borne by device manufacturers, thus acting as a restraint hindering the market growth. For instance, FDA reviews about 4,000 submissions every year and takes about 3 to 6 months in clearing most of them. In addition to this, to reduce incidences associated with the respiratory devices and ensure that the devices are safe and have the least adverse reactions, the Medicines and Healthcare products Regulatory Agency (MRHA), UK regulates and monitors the devices by restricting devices for use and sending field safety notice to correct the devices. These stringent approval processes and regulatory policies may impact the respiratory devices and equipment market.

Companies in the respiratory devices and equipment market are increasingly investing in enhanced mechanical ventilators for efficient patient management.These mechanical ventilators use artificial intelligence to improve patient management by examining, analyzing, integrating, and incorporating data from extensive sources.

These AI-enabled devices ensure consistency even in the absence of expert personnel, improve patients’ treatment, limit clinical mistakes, and predict prolonged mechanical ventilation by using artificial intelligence techniques. Some of the major companies offering intelligent mechanical ventilators such as Hamilton Medical AG, Koninklijke Philips N.V., and others.

In March 2019, the Medicines and Healthcare products Regulatory Agency (MRHA), a regulatory body for respiratory devices of the UK, sent a medical device alert to Draeger, a medical device manufacturer, on its breathing circuits VentStar Helix and Set2go products, as the breathing circuits used in conjunction with devices are not compatible.These devices impact patients’ health as cracks have formed in the breathing hose during ventilation.

MRHA sent a field safety notice to correct the device to reduce incidences associated with these devices and promote the use of hoses solely with devices that are declared as compatible in the instructions for use. Similarly, in March 2019, O-Two Medical Technologies, a Canada-based medical technology manufacturer, was sent an urgent field safety notice to stop use and return for inspection of O-Two eSeries Ventilators e700,e600, and e500 to inspect device functions, reset and analyze the data.

The countries covered in the respiratory devices and equipment market are Brazil, China, France, Germany, India, Indonesia, Japan, South Korea, Russia, the UK, USA, and Australia.
Read the full report: www.reportlinker.com/p06277193/?utm_source=GNW

About Reportlinker
ReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

__________________________

CONTACT: Clare: [email protected] US: (339)-368-6001 Intl: +1 339-368-6001

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New York, May 13, 2022 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Respiratory Devices And Equipment (Therapeutic And Diagnostic) Global Market Report 2022" - www.reportlinker.com/p06277193/?utm_source=GNW
, and CareFusion Corporation.

The global respiratory devices and equipment (therapeutic and diagnostic) market is expected to grow from $25.23 billion in 2021 to $28.97 billion in 2022 at a compound annual growth rate (CAGR) of 14.8%. The market is expected to grow to $47.86 billion in 2026 at a compound annual growth rate (CAGR) of 13.4%.

The respiratory devices and equipment (therapeutic and diagnostic) market consist of sales of respiratory devices and equipment (therapeutic and diagnostic) and related services. Respiratory devices and equipment are used to provide medication or assist a patient who is having difficulty in breathing and cannot achieve adequate oxygen levels to maintain life.

The main types of respiratory devices and equipment are diagnostic devices, therapeutic devices, and monitoring devices.The diagnostic devices are used to diagnose respiratory-related issues.

The various therapeutic devices are humidifiers, nebulizers, oxygen concentrators, positive airway pressure (PAP) devices, ventilators, and others.The diagnostic devices involved are spirometer, polysomnographs, and peak flow meters and monitoring devices are pulse oximeters, capnography, and gas analyzers.

These provide applications in chronic obstructive pulmonary disease (COPD), asthma, obstructive sleep apnea (OSA), respiratory distress syndrome (RDS), cystic fibrosis, and pneumonia. These are used by hospitals, clinics, home care settings, and ambulatory service centers.

Asia Pacific was the largest region in respiratory devices and equipment (therapeutic and diagnostic) market in 2021.Western Europe was the second-largest region in respiratory devices and equipment (therapeutic and diagnostic) market.

The regions covered in this report are Asia-Pacific, Western Europe, Eastern Europe, North America, South America, Middle East, and Africa.

The global therapeutic respiratory devices and equipment market will be driven by the increase in diseases such as Chronic Obstructive Pulmonary Disease (COPD), asthma, and lung cancer.Growth in the geriatric population, tobacco consumption, allergens, and air pollutants increase the prevalence of respiratory diseases, in turn driving the global therapeutic respiratory devices market.

According to World Health Organisation,4.9 million people die due to tobacco consumption, and smoking causes chronic obstructive pulmonary diseases (1 million deaths annually), cardiovascular and respiratory diseases (1.7 million deaths annually), and lung cancer (0.85 million deaths annually). According to an Italian journal, COPD in the U.S. is estimated to be 10% in the population aged 75 years or over. According to Asthma UK, 5.4 million people in the UK are currently receiving treatment for asthma out of these 1.1 million are children and 4.3 million are adults.

A longer duration of time taken in the approval process of the respiratory devices is restricting the respiratory devices and equipment market growth. Before a new respiratory device is introduced to the market, it takes 7.2 months for the FDA approval process, which adds to development costs to be borne by device manufacturers, thus acting as a restraint hindering the market growth. For instance, FDA reviews about 4,000 submissions every year and takes about 3 to 6 months in clearing most of them. In addition to this, to reduce incidences associated with the respiratory devices and ensure that the devices are safe and have the least adverse reactions, the Medicines and Healthcare products Regulatory Agency (MRHA), UK regulates and monitors the devices by restricting devices for use and sending field safety notice to correct the devices. These stringent approval processes and regulatory policies may impact the respiratory devices and equipment market.

Companies in the respiratory devices and equipment market are increasingly investing in enhanced mechanical ventilators for efficient patient management.These mechanical ventilators use artificial intelligence to improve patient management by examining, analyzing, integrating, and incorporating data from extensive sources.

These AI-enabled devices ensure consistency even in the absence of expert personnel, improve patients’ treatment, limit clinical mistakes, and predict prolonged mechanical ventilation by using artificial intelligence techniques. Some of the major companies offering intelligent mechanical ventilators such as Hamilton Medical AG, Koninklijke Philips N.V., and others.

In March 2019, the Medicines and Healthcare products Regulatory Agency (MRHA), a regulatory body for respiratory devices of the UK, sent a medical device alert to Draeger, a medical device manufacturer, on its breathing circuits VentStar Helix and Set2go products, as the breathing circuits used in conjunction with devices are not compatible.These devices impact patients’ health as cracks have formed in the breathing hose during ventilation.

MRHA sent a field safety notice to correct the device to reduce incidences associated with these devices and promote the use of hoses solely with devices that are declared as compatible in the instructions for use. Similarly, in March 2019, O-Two Medical Technologies, a Canada-based medical technology manufacturer, was sent an urgent field safety notice to stop use and return for inspection of O-Two eSeries Ventilators e700,e600, and e500 to inspect device functions, reset and analyze the data.

The countries covered in the respiratory devices and equipment market are Brazil, China, France, Germany, India, Indonesia, Japan, South Korea, Russia, the UK, USA, and Australia.
Read the full report: www.reportlinker.com/p06277193/?utm_source=GNW

About Reportlinker
ReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

__________________________


        

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The lungs are an essential part of the respiratory system. The respiratory system facilitates breathing and has two parts: the upper respiratory tract, which includes the airways like the nose, mouth, sinuses, and windpipe (trachea), and the lower respiratory tract, which consists of the lungs and bronchial tubes. 

The lungs’ main role is to deliver oxygen to the blood and remove carbon dioxide from the blood. Air enters the nose or mouth and passes through your windpipe and into the bronchial tubes when you breathe in. The bronchial tubes lead into the lungs and branch out into smaller tubes known as bronchioles, which end in small air sacs known as alveoli.

The alveoli are surrounded by capillaries (small blood vessels) that carry oxygen-low blood through them. Oxygen from the air in the alveoli flows into the blood, and carbon dioxide moves out of the blood and into the alveoli.

The carbon dioxide flows from the alveoli and back up through the respiratory system, where it is exhaled out of the mouth or nose.

In this article, you will learn about lung anatomy, how lungs function, and how to keep them healthy.

Igor Alecsander / Getty Images


Lung Anatomy

Though both lungs are similar in makeup, they are asymmetrical. The left lung is slightly smaller than the right lung to accommodate the heart. The right lung has three lobes—the right upper lobe, the right middle lobe, and the right lower lobe. The left lung has an upper and lower lobe.

The lungs are wrapped in pleura, a two-layer membrane. Fluid between the layers helps reduce friction when breathing.

Both lungs have a pulmonary artery, bronchial arteries, and pulmonary veins that carry blood in and out of the lungs.

The alveoli inside the lungs are small thin sacs that allow for an exchange of gases, bringing oxygen into the blood and carbon dioxide out of the blood.

Muscles around the lungs aid in breathing. These muscles include the diaphragm, a disk-shaped muscle that sits under the lungs, and the intercostal muscles that run between the ribs. Muscles in the neck and mouth also help with breathing.

Lung Function

Though it is possible to control your breathing—you can take a deep breath, a shallow breath, or even hold your breath for a short period—most breathing happens without thought.

The autonomic nervous system controls breath and works involuntarily. The system senses when you need more oxygen, such as when exercising, and makes adjustments.

The autonomic nervous system has two divisions that have different functions in breathing, which are:

  • The parasympathetic system narrows the bronchial tubes and widens the pulmonary blood vessels.
  • The sympathetic system widens the bronchial tubes to allow more air in and narrows the pulmonary blood vessels. 

To help these systems, there are various sensors throughout the body to signal the body to adjust breathing rate:

  • Sensors in the joints and muscles detect movement, which can signal to the body that you are exercising and an increase in breathing rate is necessary.
  • Sensors in the brain and blood vessels measure oxygen and carbon dioxide levels in the blood, which signals the type of breathing rate adjustment needed.
  • Sensors in the airways themselves can detect substances that may irritate the lungs, such as smoke or allergens, which may cause coughing or sneezing.

Lung Function Tests

A lung function test can determine the health of the lungs. These tests show how well the lungs work and can include:

  • Spirometry: Spirometry is the most common lung function test. The test consists of breathing in and blowing into a tube that records the volume of air inhaled and exhaled. A healthcare provider walks you through the test and has you inhale and exhale in different manners—sometimes forcefully and others at a normal rate.
  • Diffusion capacity test: During this test, a gas mixture is inhaled and then exhaled to determine how well the alveoli function at moving gases into and out of the lungs and blood.
  • Overnight pulse oximetry (OPO): Overnight pulse oximetry can detect the amount of oxygen in the blood over an extended period, mainly at night during sleep. A sensor is placed over the tip of your finger during the test, and the oxygen saturation levels (the amount of oxygen in the blood) are recorded.
  • Six-minute walk test: This test can measure how well your heart and lungs work during exercise or movement. You will walk for six minutes during the test while your heart rate, oxygen levels, and blood pressure are measured.

Respiratory Diseases Affecting the Lungs

There are various respiratory diseases that can affect the lungs and reduce their ability to function. These diseases include:

  • Asthma: Asthma can obstruct the airways, causing wheezing or difficulty breathing. While the cause of asthma is not fully understood, certain pollutants can make it worse such as tobacco smoke and air pollution.
  • Chronic obstructive pulmonary disease (COPD): "COPD" is a term used to describe a group of progressive diseases that causes damage to the tissues of the lungs. This results in a variety of symptoms from shortness of breath to chest pain, a chronic cough, and tiredness.
  • Cystic fibrosis (CF). Cystic fibrosis is a genetic condition that causes the mucus in the lungs to become sticky and disrupt normal breathing patterns.
  • Lung cancer: Cancer of the lungs is a major cause of cancer-related deaths. Cancer of the lungs can affect any part of the lung structures.
  • Pneumonia: Pneumonia is often caused by infection. It results in inflammation in the alveoli of the lungs and can cause difficulty breathing. 
  • Tuberculosis: Tuberculosis is a highly contagious bacterial infection that can damage the lungs if not treated.

Maintaining Lung Health

Taking good care of your overall health, such as by doing the following, can help maintain lung health as well:

  • Regular exercise can keep your lungs healthy and strong.
  • Seeing your healthcare provider regularly for checkups can help detect problems with the lungs early, even if you have no symptoms.
  • Quitting smoking can prevent many lung issues since smoking is the leading cause of lung cancer and COPD issues like emphysema.
  • Taking good care of yourself to minimize exposure to infections can also help prevent lung issues, including washing your hands often, getting recommended vaccinations, and avoiding being around others who are sick.
  • Avoid air pollutants by paying attention to the air quality in your area and staying indoors when air quality is bad, avoiding secondhand smoke, and limiting your exposure to chemicals in your house and at work.

Summary

The lungs play an important part in the respiratory system. Their main function is to provide oxygen to the blood and remove carbon dioxide from the blood. Various diseases can affect the lungs, including asthma, infections, COPD, and cancer. Keep the lungs healthy by avoiding pollutants, getting regular exercise, and ceasing smoking.

A Word From Verywell

The lungs are a vital part of your health. When they are working as they should they will provide the oxygen you need to enjoy life with energy and vigor. If you have difficulty breathing or any symptoms related to lung disease, it’s important to talk to your healthcare provider right away.

Frequently Asked Questions


  • What are the first signs of lung problems?

    Some of the first signs of lung problems are shortness of breath, difficulty breathing, and tiredness.


  • What role do the lungs play in the respiratory system?

    The lungs provide oxygen to the blood and remove carbon dioxide from the blood.


  • How can you take care of your lungs?

    Taking care of your overall health can help you take care of your lungs. Exercise regularly, get routine checkups and avoid inhaling pollutants that can damage your lungs.

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Introduction

Chronic obstructive pulmonary disease (COPD) is a major public health problem and is the third leading cause of death in China.1 According to Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) 2022,2 pulmonary rehabilitation (PR) as one of the effective non-pharmacological therapies was recommended in COPD patients, to improve their symptoms, activities of daily living, muscle and emotional function as well as quality of life. Although the improvements of PR were well documented, these benefits could decrease gradually over time.3,4 Therefore, researches explored long-term maintenance strategies to extend PR benefits. Based on the results of recent studies,5,6 GOLD 2022 stated that a maintenance program should be provided to patients to increase and maintain activities of daily living.2

Despite the benefits, different PR maintenance programs were also challenged by many difficulties, such as distance to obstacle,7 lower frequency8 and unsupervised maintenance exercise.9 Recently, the American Thoracic Society (ATS)/European Respiratory Society (ERS) statement recommended that tele-rehabilitation was regarded as an alternative approach to increase the long-term degree of participation for PR maintenance,10 making it more efficient and feasible. Tele-rehabilitation involves the delivery of medical rehabilitation services to patients remotely via electronic information and social media.11 For example, one study of 10 patients with COPD investigated the effectiveness of telerehabilitation maintenance indicating that the strategy can decrease the frequency of acute exacerbation of COPD, improve health status and QoL.12 Recently, an intervention of PR maintenance strategy via tele-contact provided relevant clinical benefits on reduction in risk of exacerbation of COPD, hospitalization at the end of one-year follow-up.13 Moreover, Twitter and Facebook can provide convenient visual guidance and supervision to participants, results in improving the maintenance efficiency.14 To date, accumulating evidence indicates improvement from telerehabilitation. Although the results are promising, a system review showed that QoL, and exercise capacity could be possibly improved via supervised PR maintenance (telephone or web platform) but with low strength evidence due to high risk of bias.15 Likewise, other limitations such as high dropout rate, short PR maintenance duration, small sample size or poor adherence,16,17 made the value of telerehabilitation maintenance limited.

WeChat has rapidly developed into a comprehensive information platform integrating communication, entertainment, search, office collaboration, corporate customer service and medicine in China.18 The recent study indicated that WeChat app-based education and rehabilitation could reduce the emotional dysfunction such as anxiety, depression and improve QoL in non-small lung cancer patients undergoing surgery.19 It is reasonable to apply new technology in PR maintenance management in patients with COPD. Thus, we established a new system for PR maintenance under the WeChat platform. To our knowledge, our study is the first prospective clinical trial to explore a new WeChat PR maintenance strategy to maintain the clinical improvements of an initial PR program in Tianjin, North China.

Methods

Study Design and Participants

A one-year single-center random clinical trial was conducted by Tianjin Chest Hospital to investigate the effect of home-based maintenance strategy via WeChat and hospital-based maintenance compared with usual care (ChiCTR1900021320) from January 2019 to March 2021. Patients were enrolled by respiratory department in Tianjin Chest Hospital, which is a tertiary hospital offering specialized medical care in pulmonary and cardiovascular diseases. We included patients who were 1) having a diagnosis of stable COPD in the first 4 weeks according to guideline,2 2) able to complete the PR program and questionnaire survey successfully and independently, and 3) able to use WeChat proficiently. The exclusion criteria included the following: 1) having asthma; obstructive sleep apnea syndrome; underdiagnosis of cancer; diagnosed with Alzheimer’s disease or depression and anxious disorder, 2) having severe dysfunction of the heart, liver, or kidney, 3) unavailable for exercise, 4) suffering emotional trauma in the previous 6 months such as relative death and divorce, 5) life expectancy less than 1 year, and 6) history of PR exercise for a long time (≥3 times/week, ≥20 minutes/time, persisting for more than 12 months). All of the patients were requested to perform an 8-week primary PR program. Then, eligible participants were randomized after baseline post-PR measure on a 1:1:1 basis using a computer-generated randomized sequence to two interventional groups and one control group of the following. After the generation of this sequence, the envelopes were created, numbered in the appropriate order, and contained the result of the allocation. The order of the envelopes’ number was defined based on the order of participants’ enrollment. Randomization was independent of the control of the principal investigator, thereby maintaining a minimization randomization process. Based on intervention during follow-up, patients were allocated into Group A: PR maintenance via WeChat at home, Group B: PR maintenance at hospital, or Group C: Usual care throughout 12-month observation without maintenance. All patients provided written and verbal informed consent. This study was approved by the Ethics Committees of Tianjin Chest Hospital (No. 2019KY-004-01), and was conducted in accordance with the Declaration of Helsinki.

PR Intervention

The initial 8-week PR includes; (A) upper resistance training, (B) aerobic training, (C) balance and flexibility training, (D) respiratory training, and (E) health education and self-management. The details of PR physical sessions are well documented in our previous study.6 The session of health education and self-management help COPD patients to acquire the skills they need to carry out disease-specific medical regimens, guide changes in health behavior and provide emotional support to enable them to control their disease.20

Maintenance Strategy

After the initial 8-week PR, the patients of Group A performed the maintenance exercises at home via WeChat supervision. We established a PR maintenance group-chat platform team, which consisted of respiratory specialists, physiotherapists, pharmacists, nutritionists, and nurses. The respiratory specialists and head nurse served as the team leaders and were responsible for the operation and guidance of the project. The PR guideline video was uploaded once a week by physiotherapists. The home-based PR maintenance program was requested twice a week and completion of exercise had to be uploaded in time by participants. Patients could also upload their training pictures or speeches. Other patients and PR teammates can interact with them by commenting or giving thumbs up, thus promoting not only peer support between patients but also communication between doctors and patients. Moreover, the physiotherapists were also responsible for making tailored prescriptions and sending it to the patients via private message. Patients could get the electronic PR prescription and contact a nurse online if the training program needed to be adjusted. The pharmacists were in charge of pharmacological therapy including the correct use of any prescribed respiratory medicine. Recognition of exacerbations of COPD, information for the family and social support were also provided by nurses via the WeChat platform. The PR teammates will answer the questions raised by patients in the platform by different message forms, such as text, voice, picture and video from 8am to 8pm every day. The information of health education and skill of self-management were also announced in this WeChat group regularly.

As for patients of Group B, they continued to perform the same maintenance training sessions twice a week at the out-patients department in hospital when they accomplished the primary 8-week PR. The consultant for pharmacology and nutrition was also offered by our PR team.

After the initial PR, the patients in Group C were only offered the health consultant including cigarettes cessation, long-term oxygen therapy, correct use skill of respiratory medicine, symptoms management, and nutrition without any exercise.

Assessments

The assessments below were performed before and after the integrated PR program as well as every three months in the outpatient department with the same physiotherapist during follow-up, aiming to supervise and evaluate the change of health status in COPD patients.

Primary Outcomes Measure

The numbers of acute exacerbation of COPD, hospitalizations due to acute exacerbation of COPD and ED visits, were compared among the three groups over one year following completion of the initial PR program. Acute exacerbation of COPD is defined as an acute worsening of respiratory symptoms that result in additional therapy according to GOLD.2 Hospitalizations (severe exacerbations) and Emergency Department visits (ED visits) because of acute exacerbation of COPD were also assessed.

Secondary Outcomes Measure

1) Spirometry, such as forced expiratory volume in 1 s (FEV1), FEV1% pred, forced vital capacity (FVC), FEV1/FVC%. Spirometry was measured at the baseline and post inhaling bronchodilator respectively.2

2) Physical capacity assessment: Six-minutes walking test (6MWT) will be recommended. According to protocol of American Thoracic Society,21 patients walk as long as they can in a 30-meter straight corridor in six minutes without any interruption. The valid distances they completed were recorded when they finished the test.

3) Chronic Obstructive Pulmonary Disease Assessment Test (CAT),22 CAT was used to evaluate the Health-Related Quality of Life (HRQoL) for follow-up.

4) Modified Medical Research Council scale (mMRC)23 was applied to assess the severity of breathless. The mMRC is an effective and convenient evaluation of clinical methods for rating apnea, which can be performed under different conditions for COPD patients.

5) Beck Depression Inventory (BDI) and State-trait Anxiety Inventory (STAI).24 The content of BDI includes 21 items including evaluation of nervousness, dizziness, inability to relax. STAI is aimed at measuring severity of current anxiety and tendency to be anxious.

6) Instrumental Activities of Daily Living (IADL). Measuring IADL is one of the best ways to evaluate the level of health,25 assess the progress of the disease, and evaluate the efficacy of rehabilitation or other treatments in patients with COPD.

Once any accident events of tachycardia (higher than 85% of target HR), hypoxia (pulse oxygen saturation (SaO2) is lower than 10% of baseline), hypertension (blood pressure is higher than 200/100 mmHg), and syncope were observed during exercise, patients are forbidden to continue training and given therapy immediately.

Study Procedures

The outcomes of all subjects were evaluated at baseline before primary 8-week PR, and immediately after completion of the PR program in all three groups. Then, the patients of Group A performed the maintenance exercise described above at home with WeChat supervision during 12-month follow-up, while Group B did the maintenance training at the out-patient department in hospital for one year. For Group C, only health suggestions were provided without any form of rehabilitation exercise following completion of the initial PR. The regular reviews were applied every three months during the one-year follow-up by the same physiotherapists.

Sample Size

The sample size requirements for this study were intended to provide adequate power for the analysis of the primary outcome. In the current study, the calculation of sample size was based on ANOVA repeated measurements between the three groups. From the previous study with patients with similar characteristics,26 we estimated the power calculation by using the minimum detectable difference in the number of acute exacerbations of COPD. This previous study assessed the effect of PR program on frequency of acute exacerbation of COPD before and after PR. The mean number of acute exacerbations of COPD was reduced from 4.56 in the year preceding PR to 3.18 (a mean difference (1.37) and SD (3.26), an effect of size 0.4) in the year following PR. We calculated that a sample size of 114 patients would achieve a power of 0.90, with a type-I error (α) of 0.05 (two-sided). To compensate for a potential dropout rate of 20%, 136 patients (46 patients in each group) will be enrolled.

Statistical Analysis

The Shapiro–Wilk test revealed that all data were normally distributed. Descriptive data for the three groups are presented as mean and SD for continuous variables and frequency for categorical variables. One-way analysis of variance (ANOVA) was used to compare differences among the three groups at baseline for all variables. Pair-wise Tukey’s post-hoc analysis was used to compare all pairs of variables in each group of pre- and post-initial PR. We applied repeated-measure ANOVA and multivariate ANOVA to test the differences over time in 6WMD, CAT, mMRC, BDI, SAI, TAI and between-group differences. Time to first AECOPD for each group were analyzed by Kaplan–Meier survival curves and Log rank tests. We analyzed data via SPSS, version 22.0 software (SPSS Inc., Chicago, IL, USA). A probability P-value of <0.05 was considered statistically significant.

Results

150 eligible patients with COPD who met the inclusion criteria and accomplished the baseline assessments (Table 1) undertook the primary pulmonary rehabilitation program at the out-patient department in Tianjin Chest Hospital for 2 months. At the end of the PR, 148 participants were randomized and evaluated again with the exception of two subjects who were excluded due to transportation. During the one-year observation, 3 patients were excluded due to lack of motivation in Group A, while 5 quit the maintenance PR because of transportation problems, lower exercise self-efficacy and an adverse event in Group B (Figure 1).

Table 1 Demographic and Clinical Characteristics of Patients at Baseline (N = 150)

Figure 1 Flow chart of the study population.

Effect of PR

Compared to pre-PR, the patients in all groups had statistically significant improvements in the 6MWD, mMRC, CAT and emotional evaluation at the end of primary PR (post-hoc paired t-tests), particularly the difference for change in 6MWD in Group A and Group C that exceeded 26 m which is considered a minimal clinically important difference (MICD) in patients with COPD.27 The between-group differences in each outcome measures after initial PR showed no statistical significance analyzed by one-way ANOVA (Table 2).

Table 2 The Differences of Clinical Improvements Between Pre- and Post-PR in All Three Groups

The Frequencies of Acute Exacerbation, Hospitalization, and ED Visits

In comparison with the baseline, the frequencies of acute exacerbation of COPD, hospitalization, and ED visits all showed a significant decline at the end of one-year follow-up both in Group A (3.4 ± 1.5 vs 2.6 ± 1.2, p = 0.011; 1.4 ± 0.9 vs 0.9 ± 1.2, p = 0.027; 3.1 ± 1.7 vs 1.5 ± 1.8, p < 0.001) and Group B (3.2 ± 1.3 vs 2.5 ± 1.6, p = 0.004; 1.5 ± 1.2 vs 1.0 ± 1.4, p = 0.018; 3.3 ± 1.4 vs 2.6 ± 1.2, p < 0.001), analyzed by post hoc paired t-tests. Moreover, the frequencies of AECOPD after one-year PR maintenance in Group A and Group B were both lower than Group C (2.6 ± 1.2, 2.5 ± 1.6 vs 3.5 ± 1.3, p < 0.05, respectively). Similarly, the numbers of hospitalization for AECOPD in Group A and Group B were lower than Group C (0.9 ± 1.2, 1.0 ± 1.4 vs 1.4 ± 0.9, p < 0.05, respectively). Finally, the ED visits after one-year observation in Group A were lower than Group B and Group C (1.5 ± 1.8 vs 2.6 ± 1.2, 3.1 ± 1.9, p < 0.05, respectively).

The Kaplan–Meier curves evaluating the time to first acute exacerbation of COPD during our follow-up are shown in Figure 2. In the univariate regression analysis, significant predictors of AECOPD were smoking status, exacerbation numbers in the prior year and PR (either home-based maintenance via social media or hospital-based maintenance) (Table 3). In multivariate analysis, PR is an independent predictor of lower risk for acute exacerbation of COPD in the one-year follow-up for home-based maintenance via social media (incidence rate ratio (IRR) 0.712, 95% CI 0.595–0.841; p < 0.001) and hospital-based maintenance (incidence rate ratio (IRR) 0.799, 95% CI 0.683–0.927; p = 0.002), respectively (Table 3).

Table 3 Predictors of Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Figure 2 Kaplan–Meier estimates of the time to next COPD exacerbation. Group A: PR Maintenance at home via WeChat. Group B: PR Maintenance at hospital. Group C: Usual care. The COPD exacerbation refers to all types of acute exacerbation of COPD, including mild, moderate and severe.

One-Year Follow-Up Maintenance

During one-year follow-up, the 6MWD in Group A and Group B increased over time from month 3 to month 12, compared to month 0 (p < 0.001). In contrast, the result of 6MWD in Group C showed a decreased trend from month 6, and it declined below the level of month 0 at the end of observation (p < 0.001). The between-group differences (F(2, 136)= 5.834, p = 0.025), the time effect (F(4, 544)= 178.872, p < 0.001) and the time*group interact effect of 6MWD (F(8, 544)= 88.957, p < 0.01) showed significance when analyzed by repeat-measure ANOVA (Figure 3A).

Figure 3 Patterns of change of 6MWD, mMRC, CAT (AC), BDI, SAI, TAI (DF) over study of 12-month follow-up between groups. Data shown are mean values with error bars representing SE. Circles are values for the home-based PR maintenance via WeChat group (Group A), squares are values for hospital-based PR maintenance group (Group B), triangles are values for usual care group (Group C). Month 0 is the time point when patients completed the initial 8-week PR. *Significant differences of between-group over time (p < 0.05).

Compared to month 0, the mMRC scores in Group A showed significant decrease in month 3, and then increased gradually from month 6 to month 12, but was still lower than the level of month 0 (p < 0.05). Similarly, the trend of mMRC scores in Group B showed a decline from month 3 to the end without any increase (p < 0.05). To the contrary, in Group C, the mMRC scores decreased initially and increased over time to the end (p < 0.001). The between-group differences (F(2, 136)= 23.433, p < 0.001), the time effect (F(4, 544)= 57.976, p < 0.001) and the time*group interact effect (F(8, 544)= 52.25, p < 0.001) showed significance when analyzed by repeat-measure ANOVA (Figure 3B).

The scores of CAT in Group A and Group B showed a similar trend which decreased from month 3 to month 12 (p < 0.001), while after the initial smooth decrease by month 3, the scores of CAT in Group C increased from month 6 to the end of observation. The between-group differences, the time effect and the interact effect of CAT showed significance analyzed by repeat-measure ANOVA (F(2, 136)= 12.489, p = 0.014; F(4, 544)= 150.404, p < 0.001; F(8, 544)= 20.764, p < 0.001, respectively) (Figure 3C).

During maintenance observation, BDI (Figure 3D), SAI (Figure 3E) and TAI (Figure 3F) did not show significant between-group differences over time (p > 0.05). Similarly, neither time effect (p > 0.05) nor interact effect (p > 0.05) of BDI, SAI, or TAI showed significant difference when analyzed by repeat-measure ANOVA.

Discussion

The main finding of the present study was that the PR maintenance strategy (both home-based WeChat-supervised maintenance and hospital-based maintenance) could preserve, even extend the effect of initial PR benefits on the performance of exercise tolerance, HRQL. After one-year follow-up, the frequency of AECOPD, hospitalization due to AECOPD and ED visits all showed significant decline in patients with COPD applying PR maintenance in Groups A and B, compared to the non-maintenance group. Moreover, home-based PR maintenance was as effective as the hospital-based PR maintenance and superior to non-maintenance in reducing the acute exacerbation of COPD during long-term follow-up. Finally, PR maintenance was an independent predictor of decreased risk for acute exacerbation of COPD.

In a previous study, the improvements pulmonary rehabilitation provided to COPD patients was preserved for a short term, most of the PR gains diminished over time without any maintenance.28 In the present study, we reached a similar conclusion that the effect of the initial 8-week PR provided to the patients in Group C faded gradually during the one-year follow-up. By contrast, the PR maintenance which was provided in Group A and Group B preserved, even extended, part of the benefits of initial PR at the end of follow-up. Therefore, PR maintenance strategy was recommended in GOLD 2022 recently.2 With respect to the reduction of risk for acute exacerbation of COPD in our study, the patients in PR maintenance groups were at a lower risk of deterioration than the non-PR maintenance group. This result was consistent with previous randomized controlled trials (RCT) which applied the similar long-term PR maintenance strategy.29,30 Indeed, program components including the suitable intensity of exercise, integrated skill for recognition of exacerbation, encouragement and support from family or physicians, even the nutrition and medicine information were provided to patients regularly during the maintenance follow-up. As a result, these patients taking part in and completing the structured maintenance program will have more chance to alleviate symptoms as well as decrease the risk for deterioration of COPD, hospitalization and ED visits, compared to the usual care strategy. Therefore, these findings implied that the PR maintenance strategy should be continued to be offered to patients who have a higher risk of exacerbation and more symptom burden in daily lives following an initial PR program, and as an extension of pulmonary rehabilitation. Moreover, maintenance could not only provide potential sustaining clinical improvements but also reduce the substantial healthcare cost to society.

In the last decade, studies have demonstrated the efficacy and safety of the technology-based interventions in promoting the physical activity, improving HRQL, monitoring physiological signs and reducing acute exacerbation in COPD.31–33 With the rapid development of internet technology, smart devices, and social media, information communication via network is convenient and accurate. WeChat is the most popular social network platform in China.34 In recent years, the “Internet Medical” model covers the shortage of unbalanced distribution of medical resources around the world, such as Twitter and Facebook, have been steadily applied in medical education.35,36 Likewise, WeChat has been gradually used in medical education and the follow-up of patients in China, and it has reported benefits in clinic. The recent study indicated that WeChat app-based education and rehabilitation could reduce emotional dysfunction such as anxiety, depression and improve HRQLin non-small lung cancer patients undergoing surgery.19 Another recent clinical trial demonstrated that WeChat PR strategy provided a greater improvement in HRQL, lung function, and showed better adherence.37 In the current study, we applied WeChat PR maintenance strategy in Group A. The patient-physician communications in this remote model were accomplished via smartphone applications which provided all PR maintenance components to patients and gave feedback or suggestions by clinicians according to uploaded patients’ vital signs during exercise. As a consequence, the novel remote PR maintenance model has a similar effect on clinical improvements and reduction of risk for AECOPD to the hospital-based PR maintenance group. This conclusion may be useful to inform the decision-making on resource allocation.38

Despite the clear evidence of benefit of hospital-based PR on physical activity and HRQL, the insufficient funding, imbalance resource allocation, and distance obstacle made value of traditional PR limited.39 Recently, many more studies have focused on implementing behavior-targeted interventions to improve physical activity via technology and the internet,40–42 and demonstrated the positive effect on reducing on risk for AECOPD. A systematic review from Cochrane database also illustrated that social media intervention may be effective at improving physical activity and well-being, which included 88 studies (871378 participants).14 Therefore, this novel remote maintenance model might be used to deliver alternatives to conventional PR across wide geographical areas, especially during the COVID-19 pandemic.

Although the PR is recommended2 and well documented in high-income countries’ COPD guidelines,3,43 the PR services are not widely available in low-income and middle-income countries (LIMICs) where the prevalence of COPD is higher and evidence of benefit of PR is very small.44 Whether the PR as implemented in high-income countries is the suitable model for LIMICs is also a critical question. The present study, to our knowledge, is the first clinical trial in regard to the PR maintenance via social media supervision in north China. The positive result of this research provided more evidence of PR and maintenance strategy benefits and verified the feasibility of this model in the local region. So, there was an important implication that it is necessary to explore the different forms and culturally appropriate PR program in LIMICs.

Limitations

There are several limitations to this work. First, this study is not a blinded design. The patients were given general information about the allocation and related intervention even different medical resources. Second, although the convenient and clear, the CAT and emotional function assessments could not evaluate the patients’ HRQL comprehensively, compared to St George’s Respiratory Questionnaire (SGRQ). Third, the technology applications were not familiar to elder COPD patients with likely recognition dysfunction. This led to uploaded vital sign being incorrect and made communication ineffective between patients and clinicians. Future studies need to explore more convenient and effective methods with comprehensive evaluation for PR maintenance delivery.

Conclusion

The remote PR maintenance via WeChat is effective at reducing the risk for AECOPD and keeping the improvements in 6MWD, mMRC, and CAT from decline. The remote PR maintenance via WeChat might be used to deliver alternatives to conventional PR.

Data Sharing Statement

Individual participant data that underlie the results reported in this article (tables and figures) are available after deidentification for 36 months after publication from the corresponding author Yi Li on reasonable request, and researchers should provide a methodologically sound proposal.

Acknowledgment

The authors thank Dr. Jerry Liu for improving the use of English in the manuscript.

Funding

This study was supported by the grants from China Soong Ching Ling Foundation (No. 2018MZFZY-009) and Tianjin Key Medical Discipline (Specialty) Construction Project.

Disclosure

All authors declare no competing interests.

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Exhale’s 12-week program gives people with lung disease the power to take control of their life by learning how to manage symptoms. Exhale is an IdeaPros Certified Partner.

Exhale is launching a revolutionary lung rehabilitation program offering accessibility and affordability for a life-changing service.

Anybody can log on to it themselves, they don't have to have a referral to the program.”

— Wendy Lawson, Exhale

NEW YORK CITY , NEW YORK , USA , May 10, 2022 /EINPresswire.com/ -- With input from a multidisciplinary team of experts, this comprehensive online pulmonary rehab program puts patients in charge of their disease. Exhale’s program can be done from home and yields massive improvements to health and quality of life.

Living with a respiratory problem is not easy. Exhale’s 12-week program gives people with lung disease the power to take control of their life by learning how to manage symptoms. Exhale is a Certified IdeaPros Partner.

Research supports the effectiveness of pulmonary rehab and its benefits for those suffering from lung disease. The issue for many Americans trying to access such treatment is a lack of insurance coverage. Many Americans can’t go to rehab due to a combination of costs and a lack of access, with hospitals offering the services remaining few and far between. Only about 2% of the population that could benefit from pulmonary rehab ever get to a program.

That’s where Exhale comes in.

Inventor and CEO, Wendy Lawson, began work on Exhale in 2019 to address these issues that were further exacerbated by the COVID-19 pandemic. The few rehab options grew fewer during the pandemic. Many of the existing options were removed amidst staffing issues, and concern about putting immunocompromised people in a group setting. The need for pulmonary rehab was at an all-time high as COVID-19 ensured lung health could be a matter of life and death, and it was inaccessible.

“What I decided to do was solve the issue of disparity in access and availability by creating my own online program. Anybody can log on to it themselves, they don't have to have a referral to the program. Users do their personalized program in 12-weeks, and we teach them all kinds of stuff that will benefit their quality of life.”

Exhale is a web-based app helping patients get better from the comfort of their homes. Many patients are hesitant to join a rehab program because of time or transportation concerns. And according to a survey from the Prevent Cancer Foundation (PCF), 43% of American adults missed routine medical checkups during the pandemic. Cost, fears, and inconvenience has kept many Americans away from this vital service until now.

Exhale caters to anyone with a lung condition, including post-COVID syndrome. It is the very first online lung rehab that uses personalized programs to meet individual goals. Exhale is launching with 231 videos and more content is on its way, including personalized content on an extensive list of specific conditions.

“Let's say you're a parent of a five-year-old that has asthma, and you have no idea how to administer all of their medicines; we teach you how to do that. And then we teach your child how to identify and manage their triggers for better long-term control. If you smoke, we include smoking cessation lessons. When we launch our modules for patients with lung cancer, we'll teach them pre-surgical prehab. It prepares them prior to lung surgery and supports them during the rebuilding phase. Learning how to set up your home or how to cook to optimize lung health can make a big difference in quality of life; our program includes all of these things,” said Lawson. “There's a whole slew of personalized options. It's a ton of content, but it's all really good information that is difficult to get in a five-minute block at the physician's office.”

Exhale includes a personalized program designed to help those with lung disease. Their courses help gain strength, increase activity, and control symptoms. Coursework includes: Basic Disease lessons, Medication Management, Welfare and psychological support lessons, Nutrition classes, exercise, and more.

Wendy Lawson leads a team of medical experts. She is a licensed Respiratory Care Practitioner and has a Master’s Degree in Public Health focused on Chronic Disease Epidemiology. Wendy serves on the board of the American Lung Association locally and is the Chair of the Regional board. She has dedicated her life to helping those with lung disease.

To learn more about Exhale, please visit www.joinexhale.com

Paul Fitzgerald
Salt & Pepper Media Inc.
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Introduction

Asthma is a heterogeneous chronic inflammatory disease of the airways characterized by airway hyper-responsiveness, bronchoconstriction, and airway remodeling. Asthma affects over 260 million people worldwide and was responsible for over 21 million Disability-adjusted Life Years (DALYs) in 2019,1 representing significant morbidity and economic burden. The prevalence of asthma is highest in countries with the highest socio-demographic index (SDI); however, death rates are highest in countries with low–middle SDI.1

Table 1 Overview of Integrins Involved in Asthmatic Airway Remodeling

The symptoms of asthma include wheezing, shortness of breath, chest tightness, and cough that fluctuate in frequency and intensity, as well as variable expiratory airflow restriction.2 Treatment includes targeting bronchoconstriction through the use of β2 adrenergic agonists, or some cases muscarinic receptor antagonists, and reducing airway inflammation via inhaled or oral corticosteroids. Such an approach is sufficient to control symptoms in most patients, however, some patients suffer from difficult-to-treat asthma, with uncontrolled symptoms despite good adherence to treatment. Severe asthma, defined as uncontrolled symptoms despite treatment with highest doses of inhaled corticosteroids in combination with an additional controller medication (eg, long-acting β2 agonist), affects approximately 5–10% of patients and is associated with frequent and uncontrolled exacerbations, and a long-term decrease in lung function.3–5

Remodeling of the airways contributes to airway wall thickening and has a detrimental effect on asthma. It is associated with accelerated decline in lung function, an increased rate of exacerbation in asthmatic patients, and irreversible airflow obstruction.6–8 Thickening of the airways is not limited to patients suffering from the severest forms of the disease and can be evident even in mild forms of asthma; however, the degree of thickening is associated with increased disease severity and degree of airflow obstruction.9,10 Airway remodeling is thought to play a vital role in the uncontrolled symptoms and disease burden observed in severe asthmatics. Over recent years many studies have implicated a family of cell surface receptors known as integrins in the development and progression of airway remodeling. This review aims to bring together our current knowledge of how integrins may either drive or inhibit airway remodeling in asthma, and discuss the potential utility of targeting integrins as a therapeutic strategy in severe asthma.

Airway Remodeling in Asthma

Airway remodeling is the collective term given to the structural changes that occur within the asthmatic airway. These changes include sub-epithelial fibrosis, thickening of the airway smooth muscle (ASM) layer, mucous gland hyperplasia, angiogenesis, and loss of epithelial layer integrity, all of which contribute to a thickened and stiffened airway wall. The development of airway remodeling begins early in the disease course, with structural changes being evident in preschool children with clinically confirmed wheeze, even prior to an asthma diagnosis.11–13

The underlying mechanisms driving the development of airway remodeling are largely unclear and likely to be extremely complex and multifaceted. While for many years airway remodeling was thought to result from the presence of chronic inflammation within the asthmatic airway, this has more recently been questioned. Structural changes in the airways of preschool wheezers do not correlate with inflammatory cell counts in bronchoalveolar lavage fluid.11 It is possible that different features of airway remodeling differ in the underlying mechanisms driving them. The following section will discuss the potential mechanisms responsible for the development and progression of airway remodeling in asthma.

Potential Mechanisms Driving Airway Remodeling

Airway inflammation has long been thought to drive the development of asthmatic airway remodeling. Asthma is largely driven by TH2 inflammation associated with interleukin-4 (IL4), interleukin-5 (IL5), and interleukin-13 (IL13), and TH2 inflammation remains a crucial target in asthma therapy development. However, a cluster analysis of asthmatic patients has suggested that patients with fixed airflow obstruction and evident airway remodeling have predominantly TH17 rather than TH2 driven inflammation.14

Further evidence of a link between inflammation and airway remodeling comes from in vivo and in silico models of asthma. A theoretical model of airway remodeling demonstrates that inflammation is sufficient to promote thickening of the airway wall towards the lumen, although increased thickening occurs when biomechanical contractile forces and inflammation are modeled simultaneously,15 suggesting interplay of multiple pathways. Additionally, numerous mouse models have highlighted a potential link between inflammation and remodeling. For example, Interleukin-33 (IL33) can exacerbate allergen-induced inflammation and remodeling in a mouse model,16 and M2 macrophages, which IL33 promotes polarization towards,17,18 has been associated with allergen-induced remodeling in mice.19

From the studies described above it is clear that the mechanistic link between airway inflammation and airway remodeling is still ambiguous. The fact that remodeling occurs very early in the disease course, including in young children with wheeze prior to a diagnosis of asthma,11–13 suggests that chronic inflammation may not be the sole driver of airway remodeling.

An alternative possibility is that the mechanical environment of the asthmatic airway drives remodeling changes. This was initially suggested in 2011 when Grainge et al20 demonstrated remodeling changes in response to bronchoconstriction in the absence of additional inflammation. Mechanistically, contraction of ASM cells and airways causes activation of the pro-remodeling cytokine TGFβ and downstream remodeling changes.21–23 Moreover, pharmacological inhibition of transient receptor potential vanilloid-1 (TRPV1), which can modulate ASM tone, reduces airway remodeling in vivo.24,25 Mathematical modeling has also suggested that airway contraction contributes to remodeling.15

In addition to contractile mechanical forces promoting airway remodeling it is also possible that non-contractile biomechanical forces contribute.26 ECM proteins within the asthmatic airway wall can promote proliferation of ASM cells27 and drive remodeling changes in vivo.28 Additionally, altered mechanics due to a stiffer airway wall may drive remodeling changes. Increased matrix stiffness promotes epithelial–mesenchymal transition,29 collagen production by fibroblasts,30 and ASM cell proliferation,31 all of which may contribute to airway remodelling. Recently, a link between matrix crosslinking, which stiffens ECM, and the development of asthmatic airway remodeling has been described whereby the matrix crosslinking enzyme lysyl oxidase-like-2 (LOXL2) has been implicated.32 Crucially, LOXL2 levels were increased in asthmatic ASM cells and pharmacological inhibition of LOXL2 in vivo reduced allergen-induced airway remodeling.32

Integrins

Integrins are heterodimeric transmembrane receptors that facilitate cell–cell and cell–matrix interactions. They provide a direct link between the environment outside of the cell and the cytoskeleton within the cell, and involved in the transmission of biomechanical signals. The family is composed of 24 mammalian members, made up by a variety of combinations of alpha (α) and a beta (β) subunit; there are eight distinct β subunits and 18 distinct α subunits.33 The α subunit is responsible for the ligand binding properties of integrins, while the downstream intracellular signaling events are co-ordinated by the β subunit. Some integrins can bind to only one type of ligand, while other integrins are able to recognize several ECM proteins.

Integrins can mediate bi-directional signals through the cell membrane; inside-out signalling regulates extracellular binding activity of integrins and thereby switching into active conformation. On the other hand, binding of ECM proteins on integrins activate signals that are transmitted into the cells known as outside-in signaling.33 These signaling events modulate roles in cell attachment, survival, proliferation, leukocyte trafficking, cell differentiation, cytoskeleton organization, cell migration, gene expression, tumorigenicity, and intracellular pH.

Integrins combine with multiple proteins to form integrin adhesion complexes (IAC), also known as the integrin adhesome, to activate downstream signaling pathways. To date the literature suggests such complexes involve at least 232 distinct integrin-associated proteins (IAP),34 including talin, paxillin, kindlins, filamin, vinculin, integrin-linked kinase (ILK), focal adhesion kinase (FAK), Src family protein tyrosine kinases (SFK), and GTPases of the Rho family. Such complexes can be split into four compartments: the ECM, the integrin, IAPs, and the actin cytoskeleton.34 The wide-ranging and diverse functions of just 24 distinct integrins are largely dependent on the complexity and diversity of IACs.

Several integrins are expressed within the lung and have roles in lung development, including branching morphogenesis, epithelial cell polarization, and differentiation.35,36 Expression of integrins varies across lung cell types and at varying times of development. Within the airway epithelium eight integrins are expressed, namely α2β1, α3β1, α5β1, α6β4, α9β1, αvβ5, αvβ6, and αvβ8.36–38 In some cases, integrin subunit expression in the epithelium is dramatically increased during inflammation or repair, most notably for the epithelially-restricted integrin αvβ6.37,39–41 Within the lung mesenchymal cells expression of α5β1, αvβ3, α2β1, α4β1, α5β1, αvβ5, and α7β5 have all been reported.22,42,43 Lung inflammatory cells also express integrin receptors; macrophages express β2 integrins, α4β1 and α5β1,44,45 and T lymphocytes are known to express α4β1, α5β1, αEβ7 and β2 integrins.42 Eosinophils, which have an important role in the pathophysiology of asthma, have a distinctive combination of eight integrins, α4β1, α6β1, αLβ2, αDβ2, αMβ2, αXβ2, and α4β7.46,47

The known function of integrins and integrin adhesomes make them attractive candidates for understanding how mechanical cues, including contractile forces and matrix stiffening, might influence airway remodeling processes. Furthermore, integrins are well-known for regulating leukocyte and inflammatory cell trafficking, which could also have important implications for asthma development and progression and for airway remodeling. The following section will discuss the role of integrin superfamily members in mediating specific airway remodeling processes in a variety of lung cells important to asthma pathogenesis. We have summarised how specific integrin heterodimers might be involved in asthmatic airway remodeling process in Table 1 and Figure 1.

Epithelial Changes in Airway Remodeling

The epithelial layer serves as a physical barrier to the exterior environment. As a result, it is the lungs’ first line of defence against foreign bodies inhaled during breathing. In addition, the healthy airway epithelium modulates immune responses and promotes the expulsion of inhaled particles through mucous production and cilia movement. The asthmatic airway epithelium undergoes dramatic phenotypic changes resulting in loss of epithelial integrity through epithelial shedding and increased mucous production via mucous gland hyperplasia.

Loss of airway epithelium is a well-documented phenomenon in asthma48–51 and is linked with airway hyper-reactivity.48,50 Loss of epithelial integrity occurs early in the disease course,49 and is thought to result from cellular apoptosis, senescence, and ineffective repair mechanisms.52,53 The asthmatic airway epithelium expresses markers of cellular injury/repair including increased epidermal growth factor receptor (EGFR),54,55 transforming growth factor β (TGFβ),56,57 and decreased E-cadherin.58 Furthermore, apoptosis and proliferative pathways are altered.59

Senescence of the epithelium occurs in asthma53 and may promote asthma development by compromising epithelial integrity and barrier function. Moreover, epithelial cell senescence drives thymic stromal lymphopoietin (TSLP)-induced airway remodeling.53 Crucially, airway epithelial senescence can be driven by a deficiency in integrin β4 expression in a P53 dependent manner,60 and the asthmatic human bronchial airway epithelium has reduced integrin β4 expression.61 In the ovalbumin mouse model of asthma, integrin β4 expression is reduced on the airway epithelium and is associated with structural disruption of the epithelial layer.62 Together, these studies in human asthmatic patients and animal models of asthma suggest a crucial role for β4 integrins in maintaining epithelial integrity in the airway.

In addition to loss of epithelial integrity, the asthmatic airway produces excessive quantities of mucous. MUC5AC and MUC5B are polymeric mucins that are significantly increased in the asthmatic airway and MUC5AC levels correlate with clinical measures of asthma including fractional exhaled nitric oxide (FeNO), sputum eosinophils, and airway hyper-responsiveness.63 A key driver of increased mucous production is goblet cell hyperplasia, which is evident in mild through to severe asthma.64,65 Additionally, mucous over-production can be driven by paracrine interactions with underlying airway smooth muscle cells.66 Overall, mucous gland hyperplasia and excessive mucus production can lead to mucous plugging of the airway, reduced airway lumen area, and airflow obstruction.67 Integrins have been implicated in mucous overproduction and goblet cell hyperplasia. β1 integrins have recently been shown to regulate cellular and secreted MUC5AC and MUC5B production in lung epithelial cells.68,69 Conversely, interactions between Mfge8 and integrin β3 subunits protect against allergen induced airway remodeling changes, including goblet cell hyperplasia.70

Increased Airway Smooth Muscle Mass (ASM)

Thickening of the airway smooth muscle (ASM) layer is a common and prominent feature of asthmatic airway remodeling. In the healthy airway, ASM cells are thought to play an important role in modulating respiratory airway tone. During disease processes, however, they have an important role in inflammatory and remodeling processes, releasing chemokines, pro-inflammatory and/or pro-fibrotic cytokines, and ECM proteins,22,26,71–73 which contributes to asthma pathogenesis.

In the asthmatic airway increased ASM mass appears to be driven by both increased myocyte size (hypertrophy) and increased myocyte number (hyperplasia), which are in turn associated with disease duration and severity.74 Some studies have suggested that the increase is due to hyperplasia rather than hypertrophy75 and others have suggested that hyperplasia only occurs in cases of fatal asthma.76 The causes of increased ASM mass in asthma are likely to be multifaceted. Interactions between ASM cells and airway epithelial cells can promote increased ASM cell proliferation and production of inflammatory cytokines and chemokines,77 suggesting a role for paracrine signaling between the two cell types. Furthermore, interactions between ASM cells and CD4+ T lymphocytes, known to be crucial to the pathogenesis of asthma, can increase ASM cell proliferation.78 Numerous ASM cell mitogens have been implicated in asthma, including Platelet derived growth factor (PDGF),79 TGFβ80 epidermal growth factor (EGF),78 heparin-binding EGF,81 and vascular endothelial growth factor (VEGF).82 In certain cases, such as PDGF,83 these mitogens can also promote ASM cell migration, which may contribute to the thickening of the ASM layer and expansion of the airway wall. Regardless of the underlying mechanism, during an asthma exacerbation, the thickened ASM bundle contributes to the airway-constricting capacity of the muscle84 and is thought to contribute to fixed airflow obstruction in severe asthma.

Several integrins have been linked with the contractile function of ASM cells. The fibronectin binding α5β1 integrins are involved in ASM cell contraction; functional blockade of α5β1 interrupts the function of focal adhesions, reduces interleukin-13 (IL13)-induced contraction of tracheal rings and inhibits airway hyper-responsiveness in vivo.85 Crucially, pharmacological inhibition of α5β1 had no effect on baseline tone of the smooth muscle rings and only reduced contraction in response to asthma-relevant contractile agonists, making it a potentially attractive approach for therapeutic targeting in asthma as the homeostatic functions of ASM could be preserved.85 A similar role has recently been identified for α2β1 integrins in regulating IL13-induced contraction, in this case through interrupting ASM cell tethering to collagen I and laminin-111.86

Contraction of ASM cells occurs via force transmission through polymerization and reorganization of the actin cytoskeleton. The cytoplasmic tail of β integrins binds to actin filaments through “linker” proteins such as vinculin, talin, and α-actinin, whereas the extracellular component of integrins interacts with the extracellular matrix to tether the cell.87 Force transmission between the cell and the extracellular matrix is therefore delivered by the actin–integrin–matrix complex. Actin filament polymerization and myosin activation are two concurrent biochemical mechanisms that are critical for smooth muscle contraction homeostasis, however, inhibiting actin polymerization limits smooth muscle force generation with minimal impact on myosin light chain phosphorylation.88–90 Crucially, actin-regulatory proteins are involved in regulating proliferation of smooth muscle cells,91 demonstrating how force transmission through integrins may influence cell proliferation and remodeling. Finally, TGFβ, which can be activated by ASM cells via integrins in response to reorganization of the actin cytoskeleton,22 augments ASM cell contraction in a RhoA-independent manner.92 This suggests a perpetual feedback loop whereby bronchoconstriction causes integrin-mediated TGFβ activation to promote airway remodeling, which in turn increases the contractility of the ASM cells and contributes to fixed airflow obstruction by increasing the baseline tone of the ASM layer.

In addition to promoting cell contractility through interactions with actin, integrin superfamily members are also involved in negative regulation of ASM contraction. Ligation of α8β1 integrins on ASM cells by milk fat globule-EGF factor-8 (Mfge8) proteins prevents IL13-induced ASM contraction.93 α9β1 integrins are also capable of negatively regulating ASM contraction. Loss of, or inhibition of, α9β1 integrins in mice increases airway contraction.94 These studies all highlight the importance of ASM cell interactions with matrix proteins through cell surface integrins to regulate ASM contraction and airway narrowing. As discussed previously, uncontrolled bronchoconstriction can promote airway remodeling via integrin-mediated activation of the pro-remodeling cytokine TGFβ.21–23 Taken together, it is clear that integrins have a potentially crucial role in regulating both pathological ASM contraction and downstream pro-remodeling effects, representing a direct link between uncontrolled asthma symptoms and the development of airway remodeling through a mechanobiological mechanism.

In addition to effects on ASM contraction, integrins expressed by ASM cells may also promote migration and proliferation of ASM cells, which is thought to contribute to thickening of the ASM layer and airway lumen narrowing in airway remodeling.95 Global blockade of RGD-binding integrins with a synthetic RGDS peptide attenuates allergen-induced ASM hyperplasia and hypercontractility, suggesting a crucial role for this subset of integrins in ASM remodeling.96 β1 integrins are highly expressed in ASM cells plus other mesenchymal cells in the lung, including myofibroblasts, and have recently been shown to localize key adaptor proteins at the leading edge of migrating ASM cells.97 Additionally, β1 integrins have been implicated in pro-proliferative responses of ASM cells to increasing matrix stiffness.31 α2β1, α4β1, and α5β1 have all been shown to regulate ASM cell proliferation.98 The matrix protein fibulin-5 has been implicated in this process through binding to β1 integrins to promote ASM cell proliferation via the mechanosensing YAP/TAZ pathway.99 Furthermore, laminin binding to α7β1 integrins promotes ASM cell survival and differentiation to a contractile phenotype.100 All together these studies support an important role of β1 integrins in regulating increased ASM mass in asthmatic airway remodeling.

Subepithelial Fibrosis

Subepithelial fibrosis in the asthmatic airway occurs in the lamina reticularis, just below the basement membrane, where ECM proteins such as interstitial collagens, fibronectin, tenascin, and proteoglycan accumulate.101 Subepithelial fibrosis is linked to asthma severity; collagen expression in the airway wall is higher in patients with moderate or severe asthma compared with those with mild disease,57 and the degree of subepithelial fibrosis is inversely correlated with FEV1.102 Increased deposition and decreased degradation of extracellular matrix (ECM) proteins is one of the major hallmarks of fibrosis regardless of organ or tissue type, and is primarily controlled by fibroblasts and myofibroblasts. Within the asthmatic airway, the number of myofibroblasts present correlates with the amount of collagens and tenascin detected in the subepithelial region.102 Furthermore, fibrocytes, which can differentiate into myofibroblasts, are increased in asthma and may contribute to subepithelial fibrosis.103

Information relating to a direct role for integrins in regulating matrix deposition in asthma is limited. In vitro studies have shown that treatment of ASM cells with the pro-remodeling cytokine TGFβ leads to increased fibronectin deposition via an α5β1 mediated mechanism involving ERK signaling.104 Additionally, in murine models it has been reported that interleukin-32 (IL32) reduces allergen-induced fibrosis via suppression of the integrin-FAK-paxillin signaling axis.105

Transforming growth factor-β (TGFβ) is thought to be a key driver of subepithelial fibrosis in asthma. TGFB1 mRNA is increased in bronchial biopsies from asthmatic individuals and levels correlate with the degree of subepithelial fibrosis.106 Furthermore, all three isoforms of TGFβ are increased in the asthmatic airway.56,57,107–109 TGFβ causes transdifferentiation of airway fibroblasts into highly synthetic, matrix producing myofibroblasts110,111 and increases production of matrix proteins by fibroblasts/myofibroblasts.112,113 Crucial evidence from murine animal models shows that inhibition of both TGFβ1 and 2 with isoform-specific function blocking antibodies reduced allergen-induced subepithelial collagen deposition,114 and intra-tracheal instillation of TGFβ1 is sufficient to cause subepithelial fibrosis.115 Finally, there is recent evidence suggesting that human bronchial fibroblast responses to TGFβ are altered in asthma, with pro-fibrotic responses being increased while anti-fibrotic responses are decreased.116 Together, these studies highlight a crucial role for TGFβ in regulating subepithelial fibrosis in asthma.

αvβ8 integrins are capable of activating TGFβ via recruitment of matrix metalloproteinases, which proteolytically cleave the latent TGFβ complex on the cell surface.117 Proteolytic cleavage of TGFβ has been previously reported,71,118 however, αvβ8 is the only integrin described thus far that mediates TGFβ activation via proteolysis. Importantly, expression of αvβ8 integrins is increased in asthma119 and expression of MMP-9 and MMP-8 in the airway inversely correlate with FEV1.120,121 Other cell types are capable of activating TGFβ via integrins including myofibroblasts, lung epithelial cells, and ASM cells.22,122–124 This raises the possibility that integrin-mediated TGFβ contributes to matrix deposition in the asthmatic airway, although this remains to be definitively proved.

Integrins have been implicated in inflammatory cell-mediated mechanisms of airway remodeling. Inhibiting RGD-binding integrins peptide on eosinophils using an RGDS blocks their ability to bind to ASM cells and interrupts the eosinophil-induced increased in ECM gene expression.125,126 Despite these studies it has been shown that a blockade of RGD-binding integrins, again using a synthetic RGDS peptide, reduces markers of ASM remodeling in vivo but has no effect on airway fibrosis, suggesting that this subset of integrins does not mediate subepithelial fibrosis.96 Finally a limited study has shown that collagen deposition in the asthmatic airway is inversely correlated with expression of α2 subunits on blood and CD4+ cells.

Angiogenesis

Angiogenesis refers to the process of forming new blood vessels. Increased vascularity of the asthmatic airway is a common observation and is evident in newly diagnosed asthma patients.127–129 The implications of increased vascularity on the pathogenesis of asthma and airway remodeling are still somewhat unclear. Correlations between increased vascularity and decreased lung function in asthma are inconsistent, with some reports finding a correlation128 and others reporting no link.127 Furthermore, animal models have shown that reducing angiogenesis experimentally using the inhibitor of angiogenesis, tumstatin, does not improve lung function.130 Although a link between increased vascularity and decreased lung function in asthma is still unclear, angiogenesis within the asthmatic airway wall enhances inflammatory cell recruitment and can cause edema, which may contribute to asthma pathogenesis.129

VEGF is one of the most potent activators of endothelial cell growth and promotes vascular permeability. VEGF levels in bronchial biopsies, serum, and bronchoalveolar lavage fluid are increased in asthma,131–133 and VEGF expression within airway cells correlates with the number of vessels.134 ASM cells isolated from asthmatics can drive angiogenesis via increased VEGF secretion.135 Crucially, pharmacological inhibition of VEGF signaling has shown promise in experimental models of asthma by reducing expression of growth factors, improving epithelial barrier function,136,137 and reducing markers of airway remodeling.138

Integrins have long been implicated in angiogenic processes, with the earliest descriptions demonstrating links between αvβ3 and αvβ5 and angiogenesis.139,140 Single nucleotide polymorphisms (SNPs) within the ITGB3 gene are associated with asthma pathogenesis.141 Additionally, pharmacological inhibition of αvβ3 prevents blood vessel maturation.142 However, genetic knockout of either β3 or β5 subunits does not alter vascular development.143,144

Genetic knockdown of integrin subunits has highlighted some potentially important roles in angiogenesis during development, which may also be important in disease. For example, genetic loss of integrin α5, which binds to fibronectin, leads to vascular defects and mice that are embryonic lethal, similar to the fibronectin knockout animals.145 This suggests a crucial role of α5 integrins and fibronectin in early angiogenesis. However a separate study found that inhibiting α5β1 with a small molecule inhibitor alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation and interrupts lymphatic vessel development without affecting blood vessel development.146 Finally, an important role for endothelial cell α2β1 integrin in promoting lumen formation in new capillaries has been described.147

Integrins in Airway Remodeling: Inflammation

Chronic airway inflammation is a hallmark of asthma and, as has been discussed previously in this article, has the potential to influence pro-remodeling pathways. Several integrins including α2β1, α5β1, αvβ3, and αvβ1 have been linked with increased cytokine release when ASM cells are cultured on collagen and fibronectin, suggesting that an altered mechanical environment may influence the inflammatory environment within the airway wall.148

Eosinophils are thought to be important to the pathogenesis of asthma and they express numerous integrins. Integrins have a key role in mediating migration of eosinophils from the blood into the lung, where they accumulate in asthma.149 Integrins, particularly β2 integrins such as αmβ2 and α4 integrins, have been implicated in eosinophil degranulation and inflammatory mediator release.150–152 In addition, α4 integrin binding to its ligand fibronectin via Fas antigen signaling increases the eosinophil survival, which may contribute to airway eosinophilia in asthma.153

Airway neutrophilia is associated with increased asthma severity and asthma that is refractory to corticosteroids, the backbone of asthma treatment.154 There is a paucity of research focused directly upon a potential role for integrins in driving airway neutrophilia in asthma; however, integrins, particularly β2 integrins, are well known to regulate neutrophil recruitment to sites of inflammation.155,156 Furthermore, neutrophils and their products have been implicated in lung fibrogenesis in other chronic lung diseases such as interstitial lung disease (ILD). For example αMβ2 integrins can regulate neutrophil extracellular trap (NET) formation in ILD,157 and secretory leukocyte protease inhibitor (SLPI), which inhibits neutrophil elastase, has differential effects on collagen expression in mouse lung tissue.158 Previous work has shown that integrin expression by sputum neutrophils in asthmatic patients is aberrant compared with healthy controls,159 however, whether such changes in integrin expression affect the overall activity of neutrophils in asthma and the impact this has on airway remodeling is yet to be elucidated.

Exposure to allergens causes an increase in TH2 cell infiltration and TH2 cytokine expression in asthmatic patients. TH2 cells co-ordinate allergy-induced asthmatic inflammatory responses through Th2 cytokines (IL-4 and IL-5), causing eosinophil infiltration and hyper-responsiveness of the airways.160 Airway epithelial cells, by acting as antigen presentation cells (APCs), can cause T-cell activation and proliferation, and silencing β4 integrins in asthmatic airway epithelial cells impairs their antigen presentation capacity and decreases T-cell proliferation.161 This is one possible integrin-dependent mechanism that may contribute to TH2 inflammation bias in asthmatic airways.

Therapeutic Targeting of Integrins to Impact Airway Remodeling

To date no drug has been developed that specifically targets the development and progression of airway remodeling. Corticosteroids, which are the mainstay of asthma treatment and primarily target airway inflammation, can reduce several markers of airway remodeling, including ASM proliferation,162 TGFβ expression in fibroblasts,163 and VEGF expression by epithelial cells,164 and can reconstitute epithelial structure.165 Despite these effects, airway remodeling persists in asthmatic patients despite long-term treatment with inhaled or oral corticosteroids, suggesting there is no overwhelming impact of corticosteroids on airway remodeling in asthmatic patients.

In recent years several new biological therapies have been developed and approved, particularly for the treatment of severe asthma, some of which have shown some effects on airway remodeling. Mepolizumab, a clinically approved anti-IL5 monoclonal antibody, has been shown to reduce airway wall thickness in CT scans166 and reduce matrix protein deposition in bronchial biopsies.167 Benralizumab is another monoclonal antibody that targets IL5 signaling, which computational modeling has suggested reduces ASM mass and the number of tissue myofibroblasts present in the airway wall.168 Omalizumab targets IgE for the treatment of allergic asthma and has been shown to reduce airway wall thickness when measured by computed tomography.169 Research into the effects of other new monoclonal antibody therapies such as dupilumab (anti-Il4 receptor) and reslizumab (anti-Il5) are yet to be published, however, the former studies suggest that inhibiting TH2 inflammation may reduce asthmatic airway remodeling in severe asthma patients. Whether such treatments can sufficiently reduce airway remodeling to lead to long-term positive effects on fixed airflow obstruction or slow the decline in lung function seen in asthmatics, which is thought to be driven by airway remodeling, is likely to be the focus of ongoing studies into the utility of biological therapies. Another key question that remains to be answered is whether therapeutic treatment of airway remodeling will be sufficient or whether prophylactic treatment much earlier in the disease course will be required for the biggest clinical benefit.

Research Dilemmas in Airway Remodeling

As discussed above, airway remodeling is a complex and diverse collection of structural changes involving many tissues and cell types. Despite the introduction of various new therapies for asthma in recent years including various biological treatments targeting airway inflammation, there has yet to be an effective treatment for airway remodeling. This is potentially a result of the many specific challenges associated with researching the underlying mechanisms driving airway remodeling, which were highlighted in detail in an American Thoracic Society statement in 2017,170 and which will be discussed briefly here.

Lack of Appropriate Animal Models

A major hindrance to research investigating airway remodeling and asthma pathogenesis more widely is the lack of an appropriate animal model. Mice are the most commonly used species for in vivo models of asthma and airway remodeling, however, rats, guinea pigs, and larger species including pigs, sheep, and horses are also used.171

A significant drawback to animal models of asthma is that asthma is a human disease that does not spontaneously occur within the animal kingdom, with the exception of eosinophilic bronchitis in cats and heaves in horses, both of which are obstructive airway diseases with some similarities to asthma. Animal models are therefore largely dependent upon sensitizing animals experimentally to an allergen and then delivering that allergen to the airways to elicit an allergic inflammatory response.171 Such models are advantageous when studying how allergy and/or inflammation drive features of asthma; however, as discussed above, the relative roles of these processes in driving airway remodeling is still largely unclear and so using such models to drive airway remodeling in animals may not accurately reflect the pathogenesis driving remodeling in man.

Size and anatomical differences between human lungs and the species used for models of asthma and airway remodeling also have the potential to negatively impact the utility of findings from such models. For example the human lung has a vastly greater number of branching airways compared with mouse lungs, the effect of which on the development of remodeling is unclear with our insufficient understanding of the mechanisms driving remodeling.170 Recent methodological advances in assessing airway remodeling in airways of various sizes in murine models of asthma172 may aid our understanding of the heterogeneic nature of remodeling, albeit within the confines of a rodent disease model discussed above.

Lack of Uniformity in Core Experimental and Technological Design

Aside from species differences, the ability to compare results across studies is further complicated by methodologies used to assess airway remodeling. Airway remodeling is often quantified across large- and medium-sized airways by measuring airway wall thickness; however, bronchioles and other smaller bronchi, because of their diverse components and structures, may have different impacts on the evolution of airway remodeling. Even at the cellular level, distinct morphological, synthetic, and epigenetic differences between lung compartments exist, as has been described for fibroblasts isolated from airways compared with distal lung regions.173,174 Existing whole-organ/whole-body imaging modalities do not have enough resolution to distinguish particular cell types and can only assess various degrees of wall thickness.170

Quantifying airway remodeling in human airways largely depends upon measuring indices within airway biopsy samples, or imaging modalities such as high-resolution computed tomography (HR-CT), both of which can predict fixed airflow obstruction in asthmatic patients.7,175 These techniques present challenges when attempting to study the longitudinal development and slow progression of airway remodeling in asthma patients due to either their invasive nature (biopsy) or high radiation exposure and cost (HR-CT). Several studies have suggested potential biomarkers of airway remodeling including TGFβ and periostin,176 galectin-3,177 hyaluronan,178 however, they have yet to be widely validated, which restricts their utility in clinical research. It is clear that both mechanistic studies of airway remodeling and clinical trials testing potential interventions that target airway remodeling remain incredibly difficult due to a lack of consensus on which AR index to use, cost effectiveness, safety, ability to make repeated measurements, plus sensitivity and specificity of measurement.

Concluding Remarks

As our understanding of the underlying mechanisms driving airway remodeling in asthma improves, so does our knowledge of how cell surface integrins play a critical role in the development and progression of airway remodeling. There is still much that we do not fully understand including the relative importance of mechanical and inflammatory cues to the development of airway remodeling. However, what is clear from research in recent years is that integrins may be involved in multiple aspects of airway remodeling across all lung cells types (see Figure 1). In the years to come, therapeutic targeting of airway remodeling may improve morbidity and lung function in patients with severe, uncontrolled asthma. With the advent of biological therapies in recent years we have begun to observe some positive effects on features of airway remodeling in the most severe asthmatics. Questions remain, however, about whether these effects are sufficient to produce long-term and long lasting impacts on airway remodeling that would improve fixed airflow obstruction and slow the decline in lung function that is observed in asthma. While the effects of some biologics on airway remodeling are encouraging we believe targeting airway remodeling specifically, rather than as a bi-product of targeting inflammatory pathways, will lead to the biggest clinical improvement in airway remodeling in the years to come. Such targeting could include approaches to target integrin mediated pathways since we have hopefully demonstrated in this review that integrins are integral to many pathways involved in airway remodeling pathogenesis. Targeting integrins directly to impact airway remodeling could be a useful adjunct to existing therapies that target airway inflammation to enable both fundamental features of asthma to be treated simultaneously.

Figure 1 Schematic diagram giving an overview of how different integrin heterodimers expressed by a variety of lung cell types may contribute to the development and/or progression of airway remodeling in asthma. Both environmental and cellular stimuli converge upon integrin signaling pathways in a variety of cell types to contribute to airway hyper-responsiveness and ASM thickening, mucous over-production, subepithelial fibrosis, new blood vessel formation, and airway inflammation.

Disclosure

Amanda Tatler reports grants from Medical research foundation, Asthma UK, and Biogen during the conduct of the study and personal fees from Pliant therapeutics outside the submitted work. The authors report no other potential conflicts of interest for this work.

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Several variables obtained from routine electronic health records (EHRs), including prescriptions in primary care and laboratory blood test results, are predictive of 90-day mortality following hospitalization for chronic obstructive pulmonary disease (COPD). These were among results of an analysis published in Pharmacological Research.

The researchers for the current study theorized that EHRs offer an opportunity for the development of a prognostic model representative of patients who are hospitalized with COPD, but that EHRs may not record some variables that are used in currently existing models. Although prognostic models based on EHRs can be built upon data from large numbers of patients who are treated by a broad range of health care professionals, the EHR rarely includes potentially important COPD-related information, such as patient questionnaires data related to smoking habits, severity of patients’ symptoms, and quality of life. The EHR also may not record physical examination results.

To explore the value of EHR data in predicting 90-day COPD mortality post hospitalization, the researchers conducted a retrospective cohort study among patients with an unplanned hospitalization for COPD in the NHS Greater Glasgow and Clyde area in Scotland between 2011 and 2017. The prespecified outcome of interest in the current study was all-cause mortality within 90 days of hospital discharge.


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A total of 17,973 patients with an unplanned hospitalization for COPD were included in the present study. Overall, 10,502 of the participants were women, 3703 were <60 years of age, 4231 were ≥80 years of age, and 9923 were in the most deprived quintile of Scottish Index of Multiple Deprivation (SIMD).

Comorbid conditions were usually reported during secondary care health encounters in the 90 days prior to the index admission, including hypertension (16%), diabetes (10%), atrial fibrillation (9%), prior myocardial infarction (7%), cerebrovascular disease (6%), heart failure (5%), chronic kidney injury or disease (5%) acute kidney injury (4%), peripheral vascular disease (4%), dementia (4%), and cancers other than lung cancer (4%).

Bronchodilators had been prescribed at least once in the prior year for 74% of the participants, inhaled corticosteroids for 55% of the patients, loop diuretics for 22% of the participants, and positive inotropic agents for 3% of the patients. The median duration of hospital admission was 5 days (range, 2 to 8 days), with 16% of the participants spending more than 14 days in the hospital and 7% spending more than 28 days in the hospital.

Within 90 days of hospital discharge, a total of 1003 patients died. Mortality increased linearly with age — from less than 2% in those less than 60 years of age to more than 9% in those more than 80 years of age. Additionally, mortality was higher among men than among women (6.7% vs 4.8%, respectively). Per univariate analysis, mortality was higher among those who were most affluent (7.5%) compared with patients with the most severe levels of socio-economic deprivation (5.2%) — most likely reflective of the older age of the most affluent participants.

Mortality following hospital discharge also increased linearly with length of stay. In the basic multivariable model, age, sex, and length of hospital stay were predictive of mortality, but not of social deprivation, even after adjusting for age. The multivariable model was well calibrated, with an area under the curve (AUC) of 0.702 (95% CI, 0.686-0.718).

Overall, 12 variables were identified as being strongly associated with prognosis, including age, sex, length of index hospitalization stay, previous diagnosis of cancer (excluding lung cancer) or dementia, prescription of oxygen or digoxin, neutrophil/ lymphocyte ratio, and serum chloride, urea, creatinine, and albumin, which maintained calibration with only a slight loss of discrimination (AUC, 0.806; 95% CI, 0.792-0.820).

The investigators concluded that the risk-calculator described herein might prove useful for evaluating and auditing clinical practice, thus guiding clinical management and risk-stratifying/-selecting patients to be invited to participate in clinical research.

Disclosure: One of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of the author’s disclosures. 

Reference 

Pellicori P, McConnachie A, Carlin C, Wales A, Cleland JG. Predicting mortality after hospitalisation for COPD using electronic health records. Pharmacol Res. Published online April 2, 2022. doi:10.1016/j.phrs.2022.106199

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