BOSTON, Mass. — How hard is it for people to fight off a virus? Scientists at Harvard University say it’s actually as easy as breathing, literally.

Their study reveals that the act of breathing generates immune responses that kill invading pathogens. In experiments, a “lung chip” that mimics the mechanical forces of breathing killed flu bugs. The discovery could lead to developing better medications for respiratory diseases, including COVID.

“This research demonstrates the importance of breathing motions for human lung function, including immune responses to infection, and shows that our Human Alveolus Chip can be used to model these responses in the deep portions of the lung, where infections are often more severe and lead to hospitalization and death,” says co-first author Dr. Haiqing Bai from Harvard’s Wyss Institute in a university release.

The alveoli are where the lungs and the blood exchange oxygen and carbon dioxide during the process of breathing in and out.

“This model can also be used for preclinical drug testing to ensure that candidate drugs actually reduce infection and inflammation in functional human lung tissue,” Dr. Bai adds.

Breathing helps to exercise the lungs

The average person will take more than 600 million breaths over the course of their life. They stretch and relax the lungs with each inhale and exhale, respectively. Those motions influence their development and vital functions. The study, published in Nature Communications, now shows breathing’s role in combating infection.

Researchers also identified drugs that reduce the production of inflammatory proteins called cytokines — including one approved to treat COVID-19. Coronavirus inflections can generate a “cytokine storm” that can have deadly consequences, leading to organ failure.

Replicating immune defenses

The lung chip will provide new information on how lung tissues react to respiratory viruses that have pandemic potential and test potential treatments. Dr. Bai and colleagues lined the two parallel microfluidic channels with different types of living human cells. They included alveolar lung cells in the upper channel and lung blood vessel cells in the lower channel. This recreated the interface between human air sacs and their blood-transporting capillaries.

Researchers filled the channel lined by alveolar cells with air, while supplying the blood vessel channel with a flowing culture medium containing nutrients that are normally delivered by the blood. Scientists separated the channels using a porous membrane that allowed molecules to flow between them.

The team infected these “breathing” Alveolus Chips with H3N2 influenza by introducing the virus into the air channel. They observed the development of several known hallmarks of infection, including the breakdown of junctions between cells, a 25-percent increase in cell death, and the initiation of cellular repair programs.

Infection also led to much higher levels of multiple inflammatory cytokines in the blood vessel channel. In addition, the blood vessel cells of infected chips expressed higher levels of immune cells. The results confirmed that the Alveolus Chip could mount an immune response against H3N2 that replicate what happens in the lung of human patients infected with flu virus.

To their surprise, chips exposed to breathing motions ​​had 50 percent less viral mRNA in their alveolar channels and a significant reduction in inflammatory cytokine levels compared to static chips. Genetic analysis revealed the mechanical strain activated molecular pathways related to immune defense and multiple antiviral genes. These activations reversed when the cyclical stretching stopped.

These immunofluorescence micrographs (at different magnifications) show the 3D cellular structure that develops within the alveolar channel and mimics the microstructure of human alveoli. (Credit: Wyss Institute at Harvard University)

Stress alone can trigger an immune response

“This was our most unexpected finding – that mechanical stresses alone can generate an innate immune response in the lung,” says co-first author Professor Longlong Si, now at the Shenzhen Institute of Advanced Technology in China.

A higher strain caused an increase in innate immune response genes and processes, including several inflammatory cytokines.

“Because the higher strain level resulted in greater cytokine production, it might explain why patients with lung conditions like COPD suffer from chronic inflammation, and why patients who are put on high-volume ventilators sometimes experience ventilator-induced lung injury,” Prof. Si adds.

The team is exploring the incorporation of additional cell types such as macrophages into the chips to increase their complexity and model more biological processes, such as adaptive immunity. They are also using their existing model to study the efficacy of new compounds, drugs, and biologics against flu, COVID, and other diseases.

South West News Service writer Mark Waghorn contributed to this report.

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