Researchers at National Jewish Health and collaborating institutions announced on Mar. 30 that they have discovered a key mechanism behind persistent pulmonary fibrosis and identified a potential way to reverse the disease. The findings, published in Nature Communications, show that the protein BCL-2 prevents normal lung repair by allowing scar-forming cells called fibroblasts to survive longer than they should.
Pulmonary fibrosis is a serious lung condition characterized by scarring that reduces lung function. One of the main challenges has been understanding why fibroblasts do not die off after injury but instead continue to accumulate, causing ongoing damage.
The study found that higher levels of BCL-2 in these cells enable them to evade cell death, leading to continued scarring. Researchers demonstrated that using targeted therapy to block BCL-2 reactivated natural processes for clearing out these harmful cells, reduced fibrosis, and improved lung structure and function in preclinical models.
"Our findings show that BCL-2 plays a central role in allowing harmful fibroblasts to survive and sustain fibrosis," said David Riches, PhD, head of the Division of Cell Biology at National Jewish Health and senior author of the study. "By therapeutically inhibiting this pathway, we were able to promote the clearance of these cells and restore key aspects of normal lung architecture. This opens an important new avenue for potential treatment strategies."
The research also showed that fibroblasts expressing BCL-2 develop features associated with cellular aging or senescence, which further contributes to disease progression. Analyses of human lung tissue confirmed these findings by identifying similar senescent cells in patients with pulmonary fibrosis.
"This study provides compelling evidence that resistance to cell death and the development of senescence are tightly linked in driving persistent fibrosis," said Elizabeth Redente, PhD, professor of medicine at National Jewish Health and first author of the study. "Targeting BCL-2 not only addresses fibroblast survival but also helps disrupt the underlying biology that sustains disease progression."
Treatment with a BCL-2 inhibitor significantly reduced fibrotic burden and improved oxygenation in preclinical models according to researchers' reports. These results suggest strong potential for future clinical applications.
The discovery marks an important step forward for those affected by pulmonary fibrosis as it offers hope for new treatment options targeting fundamental mechanisms behind this challenging disease.
