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Lung Chip Reveals Respiratory Immune Responses

Lung alveolus chip

Human lung alveolus chip (Wyss Institute, Harvard Univ.)

8 Apr. 2022. A study with a small chip device simulating human lung functions shows normal breathing generates immune responses that protect against respiratory diseases. Findings from the study by researchers at Harvard University’s Wyss Institute, a biomedical engineering research center in Boston, appear in today’s issue of the journal Nature Communications.

A team led by Wyss Institute research fellows Haiqing Bai and Lonlong Si — now at Shenzhen Institute of Advanced Technology in China — is seeking a better understanding of lungs’ innate immune functions, particularly for finding effective treatments for respiratory diseases including Covid-19 and influenza. Studying precise human lung functions in real time is difficult and potentially dangerous to patients, and most models offered by lab cultures, small animals, or organoids are often static and too rudimentary to offer meaningful results.

For this project, the researchers used a clear plastic microfluidic chip device that simulates dynamic lung functions. The device, about the size of a flash-memory drive, has channels with blood vessels and human tissue samples containing air sacs in the lungs known as alveoli. These air sacs are where oxygen is exchanged for carbon dioxide, but are also vulnerable to infections and inflammation from respiratory diseases.

Wyss Institute is a pioneer in developing human organ models on chips, and spun-off the company Emulate Inc. in Boston to commercialize the technology. Donald Ingber, director of the Wyss Institute and senior author of the Nature Communications paper, is a founder and scientific adviser to Emulate Inc. In Oct. 2020, Science & Enterprise reported on the Food and Drug Administration’s use of lung and other chip models from Emulate Inc. to test mechanisms for preventing Covid-19 infections.

Reduced damaging cytokine enzymes

In previous work, Wyss Institute researchers showed alveolus chips could simulate breathing with air pressure through the device to stretch and relax lung tissue channels similar to breathing. In this study, the team added H3N2 influenza A viruses into the breathing air stream through the chip. H3N2 is a virus first found in pigs in 2011, but spread to humans in the next two years. The researchers found the invading virus infected alveoli on the chip, resulting in recruitment of immune cells and production of cytokines characteristic of lung infections.

These immune responses, found on dynamic breathing lung chips but not on static tissue cultures, generate protective cell signals that reduce damaging cytokine enzymes characteristic of respiratory diseases, and limit inflammation and viral burden. In addition, blood vessels on the chip produce proteins that encourage immune system cells to attach to vessel walls, further aiding an immune response. From those findings, researchers identified two pathways as possible treatment targets for new respiratory disease therapies.

Bai notes in a Wyss Institute statement that the human lung alveolus chip can “model these responses in the deep portions of the lung, where infections are often more severe and lead to hospitalization and death.” And he adds, “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.”

A company taking advantage of the chip’s preclinical test capacity is Cantex Pharmaceuticals Inc. in Weston, Florida that develops small-molecule cancer therapies. Wyss Institute tested the company’s cancer drug azeliragon with the human alveolus chip and found the drug blocks production of inflammatory cytokines from lung infections. Those results led to Cantex in February licensing the research from Harvard University for development of the drug into a once-a-day pill to treat Covid-19 infections.

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