Researchers identifiy a promising strategy to reverse pulmonary fibrosis

Researchers at National Jewish Health and collaborating institutions have uncovered a critical mechanism driving persistent pulmonary fibrosis and identified a promising strategy to reverse it. The recent study published in Nature Communications reveals that the protein BCL-2 impedes normal lung repair and that targeting it may restore lung health.

Pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF), is a progressive and often fatal lung disease marked by scarring that limits the lungs' ability to function. A central challenge in treating the disease has been understanding why scar-forming cells, called fibroblasts, persist rather than die naturally after injury.

In this study, researchers demonstrated that elevated BCL-2 expression allows these fibroblasts to evade cell death, accumulate in the lungs and drive ongoing scarring. Importantly, the team also showed that blocking BCL-2 with a targeted therapy reactivated the body's natural cell-clearing processes, 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 revealed that BCL-2–expressing fibroblasts develop features of cellular aging, or senescence, further contributing to chronic disease progression. Analyses of human lung tissue confirmed the presence of these senescent, BCL-2–positive cells in patients with pulmonary fibrosis, underscoring the translational relevance of the findings.

"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."

Notably, treatment with a BCL-2 inhibitor significantly reduced fibrotic burden, improved oxygenation and partially restored normal lung structure in preclinical models, suggesting strong potential for future clinical translation.

These findings represent a significant step forward in understanding and potentially treating pulmonary fibrosis, offering new hope for patients facing this devastating disease.