What Is Pulmonary Fibrosis and Why Is It So Challenging?

Pulmonary fibrosis encompasses a group of lung diseases characterized by the thickening and scarring of lung tissue, which makes breathing increasingly difficult over time. The most common form, idiopathic pulmonary fibrosis (IPF), affects approximately 50,000 new patients annually in the United States, with a prevalence of around 20 to 50 cases per 100,000 people. This progressive condition leads to reduced lung function, chronic shortness of breath, dry cough, and fatigue, ultimately resulting in respiratory failure. Median survival after diagnosis is typically three to five years, making it one of the most lethal interstitial lung diseases.

The hallmark of pulmonary fibrosis is the excessive accumulation of extracellular matrix (ECM) produced by activated fibroblasts that transform into myofibroblasts. These cells, marked by alpha-smooth muscle actin (α-SMA), resist natural programmed cell death known as apoptosis, persisting long after the initial lung injury—often triggered by unknown causes, environmental exposures, or genetic factors—has resolved. In healthy lungs, fibroblasts undergo apoptosis during repair, allowing regeneration. In fibrosis, this process fails, leading to permanent scarring.

Current Treatments: Slowing Progression but Not Reversing Damage

Todays standard therapies for IPF, nintedanib and pirfenidone, are antifibrotic drugs approved by the FDA. Nintedanib, a tyrosine kinase inhibitor, targets pathways involved in fibroblast activation and proliferation, while pirfenidone, with anti-inflammatory and antifibrotic properties, reduces ECM production. Clinical trials like INPULSIS and ASCEND showed these drugs slow forced vital capacity (FVC) decline by about 50% over one year, delaying disease progression.

However, neither reverses existing fibrosis, and side effects—diarrhea, nausea, liver enzyme elevations—limit tolerability. Lung transplantation remains the only curative option but is available to few due to donor shortages and risks. Progressive pulmonary fibrosis (PPF), a broader category, affects even more patients, with higher incidence in the US than Europe. The urgent need for therapies that clear fibrotic cells and regenerate lung tissue has driven research toward novel targets like apoptosis regulation.

The Groundbreaking National Jewish Health Study on BCL-2

Researchers at National Jewish Health (NJH), the nations top respiratory institute, published a landmark study on February 28, 2026, in Nature Communications, titled "Conditional BCL-2 Expression in Fibroblasts Promotes Persistent Pulmonary Fibrosis which is Reversible by Therapeutic BCL-2 Inhibition." Led by Elizabeth F. Redente, PhD, professor of medicine, and senior author David W.H. Riches, PhD, head of the Division of Cell Biology, the work identifies B-cell lymphoma 2 (BCL-2)—an anti-apoptotic protein—as a central culprit in fibroblast persistence.Read the full study

The team used advanced mouse models where BCL-2 was conditionally overexpressed in platelet-derived growth factor receptor alpha-positive (PDGFRα+) fibroblasts, mimicking IPF pathology. This prevented apoptosis post-injury (bleomycin-induced), leading to senescent, pro-fibrotic cells that sustained scarring. Spatial transcriptomics on human IPF lungs confirmed BCL-2+ senescent myofibroblasts in fibrotic areas.

Unraveling the Mechanism: How BCL-2 Sustains Fibrosis

Step-by-step, the study elucidates BCL-2s role:

1. Injury Phase: Epithelial damage activates fibroblasts to produce ECM for provisional repair.
2. Normal Repair: Fibroblasts apoptose via intrinsic pathway (BAX/BAK activation, cytochrome c release), cleared by macrophages.
3. Fibrotic Persistence: BCL-2 overexpression blocks BAX/BAK, fibroblasts survive, senesce (p16, p21 markers), secrete SASP factors perpetuating inflammation and ECM.
4. Outcome: Rigid scar tissue impairs gas exchange.

David Riches noted, “BCL-2 plays a central role in allowing harmful fibroblasts to survive and sustain fibrosis.” Elizabeth Redente added, “Resistance to cell death and senescence are tightly linked in driving persistent fibrosis.”

Photo by Dulcey Lima on Unsplash

Proof of Reversibility: BCL-2 Inhibition Clears Fibrotic Cells

The pivotal advance: In established fibrosis models, selective BCL-2 inhibitor ABT-199 (venetoclax) reactivated apoptosis specifically in fibroblasts. Results included:

• Significant reduction in fibrotic burden (collagen via hydroxyproline, Ashcroft scoring).
• Decreased senescence markers.
• Improved lung compliance, oxygenation, and partial architectural restoration.
• Lung regeneration via epithelial proliferation.

Unlike broad inhibitors like ABT-263 (navitoclax, from NJHs 2023 JCI Insight study), venetoclax spares platelets, enhancing safety.Prior NJH research on navitoclax

Building on Prior Discoveries: NJHs Legacy in Fibrosis Research

This builds on NJHs 2023 findings where navitoclax reversed fibrosis in bleomycin and silica models by targeting BCL-2 family proteins in profibrotic fibroblasts. Human IPF fibroblasts were hypersensitive. NJH leads in ILD, hosting trials like ASPIRE (buloxibutid for IPF) and saracatinib studies. Collaborations with University of Colorado Anschutz amplify impact.

Clinical Translation: Ongoing Trials and Next Steps

A Phase 1 trial of venetoclax in IPF (NCT05976217) tests safety/efficacy, building directly on preclinical data. Broader BCL-2 inhibitors show promise in senescence-related diseases. Challenges: timing (post-peak fibrosis), selectivity, combination with nintedanib/pirfenidone. NJH emphasizes patient-centered research, with ILD program offering rehab, trials.Venetoclax IPF trial

Stakeholder Perspectives: Researchers, Patients, and Clinicians

Experts hail the shift from slowing to reversing fibrosis. Patients via Pulmonary Fibrosis Foundation express hope for disease-modifying therapies. NJHs integrated care—diagnostics, rehab, trials—positions it uniquely. Real-world data needed on diverse populations, as IPF mortality varies by age, occupation (higher in mining/construction).

Photo by Kai Gradert on Unsplash

Future Outlook: Toward Curative Therapies

BCL-2 targeting could transform PF management, especially PPF (higher US burden). Combined with senolytics, AI imaging for progression (NJH expertise), personalized medicine via genetics. Challenges: toxicity, biomarkers. Optimism high—preclinical reversal paves way for trials by 2027-2028.

National Jewish Healths innovation underscores academic-research synergy in tackling unmet needs.

Actionable Insights for Researchers and Patients

• Patients: Discuss antifibrotics, enroll in trials via NJH trials.
• Researchers: Explore BCL-2 combos, human models.
• Lung Health: Avoid exposures, exercise, vaccinate.