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New Hope for pulmonary Fibrosis Treatment: blocking a Cellular Switch Reverses Scarring in Mice

Pulmonary fibrosis is a deadly disease in which the lungs‍ become thickened and scarred, gradually losing their ability to deliver oxygen to the body. ‍Now, scientists at UC San Francisco ‍have​ identified a key cellular switch that drives ‍this process – and found a way to block it in mice.

The new ‌therapy, which appears Oct.15 in Journal of clinical Examination, works by preventing healthy lung cells from converting to a more harmful cell type. In mice with pulmonary fibrosis,‍ the treatment dramatically reduced the amount of scarring in their lungs.

“Pulmonary fibrosis has long been‌ one of the most devastating lung diseases,with⁤ very limited treatment options. We’re excited to have ​a new⁢ molecular target and begin the work to move ⁢this closer to clinical trials.”

Feroz ​Papa, MD, PhD, professor of medicine at UCSF and co-senior author ⁤of ‍the new paper

The findings also more broadly shed ‌light on how cells under stress can change their identity in harmful ways – ‌a process relevant not onyl to ‌pulmonary fibrosis but to other conditions ​where cells lose their normal function, including diabetes, neurodegeneration, ⁢and chronic liver disease.

“This‌ work is the result of many years of basic research on what cell types and molecular pathways are going awry in pulmonary fibrosis,” said co-senior author Dean Sheppard,MD,a professor of medicine at UCSF and former‍ Chief of the Division of Pulmonary,Critical Care,Allergy and Sleep Medicine.”It highlights the importance of essential ⁣science in leading ‌us to⁣ new treatments for diseases that, until now, have seemed untreatable.”

Lung cells off course

Pulmonary fibrosis affects about one ⁣in 5,000 people, most frequently enough ​striking older adults. The disease can appear without warning or after certain environmental ‍exposures, infections, or⁤ chemotherapy. With a median survival of only about five years after diagnosis, pulmonary fibrosis is as deadly as advanced lung‌ cancer – yet it has far fewer treatment options.

In recent years, scientists have shown that pulmonary fibrosis is caused by ​an ⁣abnormal repair process in the lungs. Normally, lung cells known as alveolar type 2⁢ (AT2) cells help keep the air sacs healthy and can ‌transform into other cell types to repair damage. But in pulmonary fibrosis, ‍many AT2 cells ⁢get stuck halfway through this transformation, creating “in-between” cells that don’t ‍function properly⁤ and⁤ rather release signals that worsen scarring.

In the new ⁣work, the UCSF team found that a protein known as IRE1α is directly responsible for pushing AT2 cells into this ​dangerous limbo. ⁤IRE1α ⁢normally senses when proteins aren’t‌ folding correctly​ inside cells – one ​sign that the cells ⁤are under⁣ abnormal stress. The new ⁢study showed that‍ in response to this signal, ‌IRE1α turns on a process called RIDD, in which it shreds ⁣certain genetic instructions – like ripping up blueprints – so the cell can’t make the corresponding ⁢proteins.