What question did this study set out to answer?

The research investigates whether nintedanib increases apoptosis in pro-fibrotic fibroblasts when combined with ABT-199 to reverse pulmonary fibrosis.

March 14, 2026

Nintedanib increases BCL-2 in fibrotic fibroblasts enhancing ABT-199 apoptosis and fibrosis resolution

Key Points

The research investigates whether nintedanib increases apoptosis in pro-fibrotic fibroblasts when combined with ABT-199 to reverse pulmonary fibrosis.
Treated healthy and PF-ILD fibroblasts with nintedanib and measured BCL-2 family expression.
Analyzed apoptosis in fibroblasts and precision cut lung slices after treatment with ABT-199 and nintedanib.
Assessed treatment outcomes in mice with bleomycin-induced progressive fibrosis using combination therapy.
Nintedanib treatment elevated levels of pro-apoptotic BIM and anti-apoptotic BCL-2 in PF-ILD fibroblasts.
ABT-199 significantly increased fibroblast apoptosis in vitro, which was enhanced by nintedanib.
Combination therapy significantly reduced fibrosis in mice by inducing apoptosis in pathogenic fibroblasts and transitional epithelial cells.

Abstract

Abstract Rationale Progressive fibrosing interstitial lung diseases (PF-ILDs) have a large global impact and there is a pressing need to develop new therapies. Objectives We investigate if nintedanib augments apoptosis of pro-fibrotic fibroblasts induced by BCL-2 inhibition with ABT-199, and if combination therapy reverses pulmonary fibrosis. Methods Healthy and PF-ILD fibroblasts were treated with nintedanib and BCL-2 family member expression was measured. Fibroblasts and precision cut lung slices (PCLS) were analyzed for apoptosis after ABT-199 and nintedanib treatment. Therapeutic intervention with ABT-199 and nintedanib in mice with repetitive bleomycin-induced progressive pulmonary fibrosis were assessed for pro-fibrotic fibroblast and aberrant transitional epithelial cell apoptosis, lung collagen content, longitudinal oxygen saturation and micro-CT disease burden. Measurements and Main Results Nintedanib treatment increased expression of pro-apoptotic BIM and anti-apoptotic BCL-2 in PF-ILD primary fibroblasts. There was significantly increased apoptosis of fibroblasts in vitro after ABT-199. This was augmented after nintedanib co-treatment both in PF-ILD fibroblasts and PCLS. ABT-199 significantly improved fibrosis in mice, which was further enhanced after nintedanib co-treatment, by targeted apoptosis of pathogenic fibroblasts and transitional epithelial cells. Conclusions The pro-apoptotic effects of ABT-199 were increased with nintedanib co-treatment and reversed fibrosis in mice. Combination treatment induced pro-fibrotic fibroblast and aberrant transitional epithelial cell apoptosis. These studies highlight a new mechanistic strategy to treat PF-ILD.

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