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.
Cooley et al. (2026) studied this question.