Inhibition of antiapoptotic BCL-2 proteins with ABT-263 induces fibroblast apoptosis, reversing persistent pulmonary fibrosis
Joseph C. Cooley, Nomin Javkhlan, Jasmine A. Wilson, Daniel G. Foster, Benjamin L. Edelman, Luis A. Ortiz, David A. Schwartz, David W.H. Riches, Elizabeth F. Redente
Joseph C. Cooley, Nomin Javkhlan, Jasmine A. Wilson, Daniel G. Foster, Benjamin L. Edelman, Luis A. Ortiz, David A. Schwartz, David W.H. Riches, Elizabeth F. Redente
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Research Article Cell biology Pulmonology

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.

Authors

Joseph C. Cooley, Nomin Javkhlan, Jasmine A. Wilson, Daniel G. Foster, Benjamin L. Edelman, Luis A. Ortiz, David A. Schwartz, David W.H. Riches, Elizabeth F. Redente

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Figure 7

ABT-263 reduces fibrotic fibroblasts in silicotic nodules and reverses fibrosis in silicosis.

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ABT-263 reduces fibrotic fibroblasts in silicotic nodules and reverses f...
(A) Schematic of silica treatment, tamoxifen dosing, ABT-263 treatment, and harvesting schedule. Quantitation of (B) PDGFRα+ (C) α-SMA TdTm+, and (E) Col1a1-GFP+ fibroblasts. (D and F) Representative immunofluorescence images of frozen sections (n = 2 per group): α-SMA TdTm+ (red), Col1a1-GFP+ (green), and DAPI (blue). (G) Hydroxyproline content of lungs, (H) semiquantitative histology scoring, and (I) representative trichrome images after vehicle or ABT-263 treatment. (J) Nonaerated lung volume as measured by micro-CT, with representative (K) axial images (red arrows indicate disease) and (L) 3D reconstructions (nonaerated lung in blue, aerated lung in gray). n = 3–13 mice per group. Graphed as scatterplot with bar, mean ± SEM, or time-course line graph with mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, 2-tailed t test with Welch’s correction. Total magnification with objective 200×, 2× (upper panels), 20× (lower panels).