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Drugs seem to help regenerate mouse lungs damaged by cigarette smoke

Two clinically available drugs have shown promise in restoring the regenerative capacity of mouse lung cells, suggesting they could be used to treat chronic obstructive pulmonary disease

Health 23 March 2022

Diseased lung scan

A false colour CT scan showing lungs (black) and damaged tissue (blue/green)

GCA/SCIENCE PHOTO LIBRARY

Two clinically available drugs may help regenerate mouse lungs that have been damaged by cigarette smoke. The preliminary findings suggest the drugs could eventually be used to reverse lung damage in people with chronic obstructive pulmonary disease (COPD), which currently has no cure.

COPD is the third leading cause of death worldwide after heart disease and stroke, and can result from smoking, air pollution or genetics. It involves an excessive immune response that irreversibly damages the lungs, leading to shortness of breath, chest tightness and elevated mucus levels in them.

“The problem with COPD at the moment is that we do not have a way of preventing the progression of disease and the decline in lung function. We only have ways to treat symptoms, for example, using anti-inflammatory drugs or inhaled bronchodilators [which relax lung muscles and widen the airways],” says Reinoud Gosens at the University of Groningen in the Netherlands.

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COPD damages so-called epithelial progenitor cells that normally regenerate the lining of the lungs, meaning they cannot repair themselves. Previous efforts at treating this have mainly focused on invasive cellular therapies such as stem cell implants, which provide a source of progenitor cells.

A drug-based treatment could be easier to use on a larger scale, either alone or in combination with other therapies. To identify one, Gosens and his colleagues analysed data previously collected from the lung tissue of people with COPD and mice exposed to cigarette smoke, as well as data from healthy people and mice, to find out which genes were more or less active in diseased lung tissues compared with healthy controls.

This allowed them to identify two proteins in epithelial progenitor cells that contributed to the disease and could be targeted using two existing drugs: iloprost, which is used to treat high blood pressure in lung arteries, and mioprostol, used to heal stomach ulcers.

To test these drugs, the team exposed mice to cigarette smoke for four months. Lung progenitor cells were then extracted from the mice and grown in a gel for 14 days, in dishes each containing one of the drugs, or control dishes with no drug.

“You take the progenitor cells and place them in a gel, then they form these mini-lung structures known as organoids,” says Gosens.

By assessing how many organoids formed in the absence or presence of the drugs, the team found that both drugs appeared to fully restore the regenerative capacity of the progenitor cells, which decreased after exposure to cigarette smoke. The team also treated the mice with the drugs during a week of cigarette smoke exposure and found they had the same beneficial effect on subsequently extracted lung cells.

“Compared to other drugs that can support lung regeneration in animals, the big benefit of the drugs we’ve identified is that they’re already used to treat other conditions, so we know that they are safe and they are similarly effective,” says Gosens.

Through further analysis, the team revealed that the drugs probably work by reinstating the circadian clocks in lung cells, which are disrupted by smoke exposure.

However, while organoid formation can indicate the regenerative potential of cells, further work is needed to confirm that the drugs really do kick-start the true regenerative process.

“The idea behind this work is wonderful. I’m really delighted to see people working on regenerative power using drugs in COPD. However, the model uses mice aged at about 20 human years, whereas typical COPD patients are around 50 and we know regenerative power slows with age. Better models are needed to really establish therapeutic potential,” says Rolf Ziesche at the Medical University of Vienna, Austria.

Journal reference: Science Advances, DOI: 10.1126/sciadv.abj9949

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