Lung-directed treatment with isthmin 1 (ISM1) — a soluble signaling molecule naturally present in the lungs — reduced lung inflammation, suppressed emphysema development, and preserved lung function in a mouse model of chronic obstructive pulmonary disease (COPD), a study shows.

Emphysema is a severe form of COPD marked by damage and abnormal enlargement of the alveoli, the tiny lung air sacs responsible for gas exchange.

The beneficial effects of ISM1 were associated with the death of pro-inflammatory alveolar macrophages, a type of alveoli-resident immune cell implicated in COPD. ISM1 was found to bind to a receptor protein highly present at the surface of these pro-inflammatory immune cells, promoting their death.

“By directly targeting pro-inflammatory AMs [alveolar macrophages] using recombinant ISM1 protein, our novel treatment suppresses the root cause of COPD, and opens up the possibility of developing this into a viable treatment for this debilitating disease that affects many patients around the world,” Ruowen Ge, PhD, the study’s senior author, said in a press release.

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Ge is an associate professor in the biological sciences department at the National University of Singapore (NUS)’s Faculty of Science.

A potential therapy based on this approach is now being tested in preclinical studies.

“These findings not only provide a new avenue to develop novel and effective [therapies] for COPD, but also warrant studies of ISM1 in other inflammatory respiratory diseases,” Fred Wong, PhD, one of the study’s authors and a professor in the pharmacology department at NUS Yong Loo Lin School of Medicine, said.

The study, “ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis,” was published in Proceedings of the National Academy of Sciences.

COPD, associated mainly with long-term exposure to irritants such as cigarette smoke, is marked by excessive airway inflammation and abnormal lung tissue repair and remodeling, often resulting in the progressive destruction of the alveoli.

People with COPD “have difficulty breathing which hinders their ability to work or exercise,” and “affects their heart function too,” Ge said. “COPD is a very dangerous condition, but public awareness of it is very low.”

Alveolar macrophages are a type of immune cell that reside in the alveoli and act as the first line of defense in the lungs, helping clear the alveoli of infectious, toxic, or allergic particles. These cells can have both pro- and anti-inflammatory properties, but in COPD there is an increase in their pro-inflammatory subset, driving the pro-inflammatory state that characterizes the disease.

While the key role of pro-inflammatory AMs in COPD is well-established, there are no approved therapies targeting this subset of cells to reduce lung inflammation and suppress further lung damage effectively.

Ge and Wong, along with colleagues in Singapore and South Korea, discovered pro-inflammatory AMs’ survival is regulated by a lung resident signaling molecule called ISM1.

ISM1 is a secreted protein that has been shown to have anti-cancer and pro-cell-death effects. These were found to involve ISM1’s binding to cell surface GRP78 (csGRP78), a receptor protein present at high levels on the surface of cancer cells.

In the current study, researchers found that mice genetically modified to lack ISM1 had increased numbers of pro-inflammatory AMs, sustained lung inflammation, progressive emphysema, and significant lung function decline.

These features resembled those of COPD, even without exposure to irritants, suggesting ISM1 may have a protective role in COPD.

Further analyses revealed variable levels of csGRP78 in alveolar macrophages of healthy lungs, but an increase in csGRP78-enriched AMs in ISM1-deficient mice, in a mouse model of cigarette smoke-induced COPD, and in the lungs of COPD patients.

AMs with high levels of csGRP78 were found to mostly produce MMP-12, a protein known to drive inflammation and emphysema in COPD, indicating that these cells are pro-inflammatory.

This suggested that csGRP78-high pro-inflammatory AMs may be the main target of ISM1 in the lungs, and that treatment with this signaling molecule may lead to therapeutic benefits in COPD.

Researchers evaluated the effects of administering a lab-made version of ISM1 directly into the airways via droplets, or tiny liquid drops, in a mouse model of cigarette smoke-induced COPD and in mice lacking ISM1.

ISM1 treatment significantly reduced the number of csGRP78-high pro-inflammatory AMs, suppressed inflammation, prevented emphysema from developing, and preserved lung function in both mice.

High levels of ISM1 were also found to be significantly associated with greater alveolar macrophage death in human lungs, “suggesting similar function of ISM1–csGRP78 in human lungs,” the researchers wrote.

These findings indicate that ISM1 “is a lung resident anti-inflammatory protein that selectively triggers [cell death] of AMs that harbor high levels of its receptor cell-surface GRP78,” the research team wrote.

Results also show that regulating alveolar macrophage death “is an important physiological mechanism for maintaining lung [balance] and [demonstrates] the potential of pulmonary-delivered rISM1 to target csGRP78 as a therapeutic strategy for COPD,” the researchers wrote.

Ge and her team plan to study whether ISM1 could be a potential therapy for other inflammatory respiratory disorders such as acute lung injury, lung fibrosis, and asthma, and to identify the best method to administer such therapeutics.

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