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

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 profibrotic 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 were analyzed for apoptosis after ABT-199 and nintedanib treatment. Therapeutic interventions with ABT-199 and nintedanib in mice with repetitive bleomycin-induced progressive pulmonary fibrosis were assessed for profibrotic fibroblast and aberrant transitional epithelial cell apoptosis, lung collagen content, longitudinal oxygen saturation, and micro-computed tomography disease burden.

MEASUREMENTS AND MAIN

RESULTS

Nintedanib treatment increased expression of proapoptotic BIM and antiapoptotic 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 precision-cut lung slices. 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 proapoptotic effects of ABT-199 were increased with nintedanib co-treatment and reversed fibrosis in mice. Combination treatment induced profibrotic fibroblast and aberrant transitional epithelial cell apoptosis. These studies highlight a new mechanistic strategy to treat PF-ILD.