Two clinically available drugs have shown promise in restoring the regenerative capacity of lung cells in mice, suggesting they could be used to treat chronic obstructive pulmonary disease
March 23, 2022
Two clinically available drugs may help regenerate mouse lungs damaged by cigarette smoke. Preliminary findings suggest that these drugs could eventually be used to reverse lung damage in patients with currently incurable chronic obstructive pulmonary disease (COPD).
Chronic obstructive pulmonary disease is the third leading cause of death globally after heart disease and stroke, and may be caused by smoking, air pollution or genetics. It involves an excessive immune response that irreversibly damages the lungs, leading to shortness of breath, chest tightness and increased mucus levels.
“The problem with COPD right now is that we have no way of preventing the progression of the disease and the decline in lung function. We only have ways to treat the symptoms, such as using anti-inflammatory drugs or inhaled bronchodilators [which relax lung muscles and widen the airways],”Say Reynolds Gosens at the University of Groningen in the Netherlands.
COPD damages so-called epithelial progenitor cells that normally regenerate the lung lining, meaning they cannot repair themselves.Previous efforts to treat this condition have focused on invasive cell therapies such as stem cell implantwhich provides a source of progenitor cells.
Drug-based treatments may be easier to use on a large scale, either alone or in combination with other therapies. To identify one, Gosens and his colleagues analyzed data previously collected from lung tissue from COPD patients and mice exposed to cigarette smoke, as well as data from healthy humans and mice, to find out which genes were involved in the disease. More or less active tissue in the lungs compared to healthy controls.
This allowed them to identify two proteins in epithelial progenitor cells that cause the disease, and could be targeted with two existing drugs: iloprost, used to treat pulmonary hypertension, and misoprostol, used to treat gastric ulcers .
To test the drugs, the team exposed mice to cigarette smoke for four months. Lung progenitor cells were then extracted from the mice and grown in gels for 14 days, in each dish containing one of the drugs, or in control dishes without the drug.
“You put progenitor cells in a gel, and they form these tiny lung structures called organoids,” Gosens said.
By assessing how many organoids were formed in the absence or presence of the drugs, the team found that both drugs appeared to fully restore the progenitor cells’ regenerative capacity, which declined after exposure to cigarette smoke. The team also treated mice with the drugs during a week of cigarette smoke exposure and found that they had the same beneficial effect on lung progenitor cells that were subsequently extracted.
“The biggest benefit of the drugs we’ve found over other drugs that can support lung regeneration in animals is that they’re already used to treat other diseases, so we know they’re safe and just as effective,” said Gosens.
Through further analysis, the team found that the drugs may work by restoring biological clocks in lung cells that are disrupted by exposure to smoke.
However, while the formation of organoids can indicate the regenerative potential of cells, further work is needed to confirm that these drugs indeed initiate the real regeneration process.
“The idea behind this work is great. I’m really excited to see people using drugs in COPD to study regenerative capacity. However, the mice used in this model are about 20 years old, and a typical COPD patient is about 50 years old. Years old, we know that regenerative capacity slows down with age. Better models are needed to really establish therapeutic potential,” said Rolf Zisher at the Medical University of Vienna, Austria.
Journal references: scientific progress, DOI: 10.1126/sciadv.abj9949
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