Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis

Abstract

Patients with progressive fibrosing interstitial lung diseases (PF-ILDs) carry a poor prognosis and have limited therapeutic options. A hallmark feature is fibroblast resistance to apoptosis, leading to their persistence, accumulation, and excessive deposition of extracellular matrix. A complex balance of the B cell lymphoma 2 (BCL-2) protein family controlling the intrinsic pathway of apoptosis and fibroblast reliance on antiapoptotic proteins has been hypothesized to contribute to this resistant phenotype. Examination of lung tissue from patients with PF-ILD (idiopathic pulmonary fibrosis and silicosis) and mice with PF-ILD (repetitive bleomycin and silicosis) showed increased expression of antiapoptotic BCL-2 family members in α–smooth muscle actin–positive fibroblasts, suggesting that fibroblasts from fibrotic lungs may exhibit increased susceptibility to inhibition of antiapoptotic BCL-2 family members BCL-2, BCL-XL, and BCL-W with the BH3 mimetic ABT-263. We used 2 murine models of PF-ILD to test the efficacy of ABT-263 in reversing established persistent pulmonary fibrosis. Treatment with ABT-263 induced fibroblast apoptosis, decreased fibroblast numbers, and reduced lung collagen levels, radiographic disease, and histologically evident fibrosis. Our studies provide insight into how fibroblasts gain resistance to apoptosis and become sensitive to the therapeutic inhibition of antiapoptotic proteins. By targeting profibrotic fibroblasts, ABT-263 offers a promising therapeutic option for PF-ILDs.

Inflammasome activation and metabolic remodelling in p16‐positive aging cells aggravates high‐fat diet‐induced lung fibrosis by inhibiting NEDD4L‐mediated K48‐polyubiquitin‐dependent degradation of SGK1

“…Treatment with senolytic drugs or gene therapy to eliminate senescent cells has been shown to alleviate pulmonary fibrosis 6,10 . ABT‐263 is a potential senolytic drug that possesses anti‐aging and anti‐profibrotic properties 11 . Indeed, bleomycin‐induced pulmonary fibrosis was previously found to be ameliorated by ABT‐263 treatment through inhibition of cellular senescence and attenuation of the expression of mitochondrial anti‐viral signalling proteins and their signalling pathways 12 .…”

“…Indeed, bleomycin‐induced pulmonary fibrosis was previously found to be ameliorated by ABT‐263 treatment through inhibition of cellular senescence and attenuation of the expression of mitochondrial anti‐viral signalling proteins and their signalling pathways 12 . Mouse models of progressive fibrosing interstitial lung diseases are also alleviated by ABT‐263 treatment through the induction of fibroblast apoptosis, decreased number of fibroblasts and a reduction in lung collagen levels 11 . Thus, senescent cells and cellular senescence‐related signalling pathways could be new targets for the treatment of pulmonary fibrosis.…”

“…6,10 ABT-263 is a potential senolytic drug that possesses anti-aging and anti-profibrotic properties. 11 Indeed, bleomycin-induced pulmonary fibrosis was previously found to be ameliorated by ABT-263 treatment through inhibition of cellular senescence and attenuation of the expression of mitochondrial anti-viral signalling proteins and their signalling pathways. 12 Mouse models of progressive fibrosing interstitial lung diseases are also alleviated by ABT-263 treatment through the induction of fibroblast apoptosis, decreased number of fibroblasts and a reduction in lung collagen levels.…”

“…12 Mouse models of progressive fibrosing interstitial lung diseases are also alleviated by ABT-263 treatment through the induction of fibroblast apoptosis, decreased number of fibroblasts and a reduction in lung collagen levels. 11 Thus, senescent cells and cellular senescence-related signalling pathways could be new targets for the treatment of pulmonary fibrosis.…”