Researchers have been trying for decades to stop the cells that damage the lung in people with pulmonary fibrosis. Now a team of Columbia and UCSD researchers may have found a clever solution that sidesteps the difficulty in stopping the cells and simply blocks the cells' creation.
In their new study, published Feb. 5 in Nature, the researchers uncovered the origins of the destructive cells-which has stumped the field for years-and then identified a way to shut down their production.
"Not knowing the sources of these pathological cells has really hampered the development of therapies that could put a stop to this disease, so there's been an intense effort to find them," says Jianwen Que, professor of medicine at Columbia University Vagelos College of Physicians and Surgeons, who co-led the study. "It may take years to translate our findings, but we hope they will lead to more effective treatments."
What is pulmonary fibrosis?
Pulmonary fibrosis can develop following a lung injury, including COVID-19, but most cases arise without any clear cause.
Once diagnosed, the disease rapidly damages the lung, and patients usually die from respiratory failure within two to five years. Two drugs approved in the last decade can slow the disease but cannot stop it.
The cells that cause the lung damage develop from healthy lung cells but are driven to deposit excessive amounts of scar tissue in the lung. "Ironically, these cells are trying to repair lung injuries, but they go too far," Que says. "The scar tissue they produce increasingly encases the lung's air sacs in a stiff matrix. The lung literally becomes too hard to breathe."
Enhanced tracing reveals cell origins
Many types of healthy lung cells have been proposed as sources of the pathological cells in pulmonary fibrosis but definitive proof-only possible with cell lineage tracking-has been missing.
Que and his colleagues used advanced tracking methods that utilize RNA sequencing of individual cells for more precise identification. These techniques had not been systematically deployed before because mouse lines to study the possible contribution of all suspected cellular sources were not available.
With new mouse lines created for the study, the researchers found that pathological cells spring from normal fibroblasts, marked with leptin receptors, in the lung's air sacs.
Canceling pathological cells
With a major source of pathological cells identified, the researchers were then able to learn that a transcription factor called Runx2 plays a critical role in the conversion of normal fibroblasts into pathological cells. Disabling the Runx2 gene in mice reduced the amount of fibrotic tissue in the lung by about 50%.
Disabling the Runx2 gene in mice blocked the conversion and reduced the amount of fibrotic tissue in the lung by about 50%. The researchers also found evidence that Runx2 plays an important role in pathological fibroblasts taken from patients with pulmonary fibrosis.
"Taken together, our study suggests Runx2 is a potential therapeutic target for preventing or treating pulmonary fibrosis," Que says, "and gives researchers a platform to find even more opportunities to prevent the aggressive progression of this disease."
