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

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

  • JCI Insight. 2023 Feb 8;8(3):e163762. doi: 10.1172/jci.insight.163762.
Joseph C Cooley 1 2,  Nomin Javkhlan 3,  Jasmine A Wilson 3,  Daniel G Foster 4,  Benjamin L Edelman 3,  Luis A Ortiz 5,  David A Schwartz 2 6,  David Wh Riches 2 3 4 6 7,  Elizabeth F Redente 2 3 4
Affiliations

Affiliations

  • 1 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado, USA.
  • 2 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 3 Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.
  • 4 Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 5 Department of Environmental and Occupational Health, Graduate School of Public Health at the University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • 6 Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
  • 7 Department of Research, Veterans Affairs Eastern Colorado Health Care System, Aurora, Colorado, USA.
PMID: 36752201 DOI: 10.1172/jci.insight.163762
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.

Keywords

Apoptosis pathways; Cell Biology; Fibrosis; Mouse models; Pulmonology.

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