Academic Journal
Nintedanib increases BCL-2 in fibrotic fibroblasts, enhancing ABT-199 apoptosis and fibrosis resolution.
| Τίτλος: | Nintedanib increases BCL-2 in fibrotic fibroblasts, enhancing ABT-199 apoptosis and fibrosis resolution. |
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| Συγγραφείς: | Cooley JC; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO, United States.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Penick SK; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO, United States., Wilson JA; Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, United States., Javkhlan N; Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, United States., Foster DG; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Edelman BL; Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, United States., Schott CA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Humphries SM; Department of Radiology, National Jewish Health, Denver, CO, United States., Lynch DA; Department of Radiology, National Jewish Health, Denver, CO, United States., Schwartz DA; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.; Department of Research, Veterans Administration Eastern Colorado Healthcare System, Aurora, CO, United States., Riches DWH; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.; Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, United States.; Department of Research, Veterans Administration Eastern Colorado Healthcare System, Aurora, CO, United States., Redente EF; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.; Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, United States.; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States. |
| Πηγή: | American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2026 Aug 01; Vol. 74 (8), pp. 1103-1113. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Thoracic Society Country of Publication: England NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: [New York, NY : The Association, [c1989- |
| Ιατρικοί όροι (MeSH): | Indoles*/pharmacology , Apoptosis*/drug effects , Fibroblasts*/drug effects , Fibroblasts*/metabolism , Fibroblasts*/pathology , Sulfonamides*/pharmacology , Proto-Oncogene Proteins c-bcl-2*/metabolism , Bridged Bicyclo Compounds, Heterocyclic*/pharmacology , Pulmonary Fibrosis*/drug therapy , Pulmonary Fibrosis*/pathology , Pulmonary Fibrosis*/metabolism, Lung/pathology ; Lung/drug effects ; Lung/metabolism ; Idiopathic Pulmonary Fibrosis/drug therapy ; Animals ; Mice ; Mice, Inbred C57BL ; Humans ; Bleomycin ; Male |
| Περίληψη: | 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. (© The Author(s) 2026. Published by Oxford University Press on behalf of the American Thoracic Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.) |
| Σχόλια: | Comment in: Am J Respir Cell Mol Biol. 2026 Aug 1;74(8):988-990. doi: 10.1093/ajrcmb/aanag105.. (PMID: 42113898) |
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| Grant Information: | American Thoracic Society; R01HL158668 United States GF NIH HHS; R01 HL158668 United States HL NHLBI NIH HHS; R01HL149836 United States GF NIH HHS; I01 BX005295 United States BX BLRD VA; K08HL171850 National Institue of Health; R01HL147860 National Institue of Health; I01BX005295 United States VA VA; K08 HL171850 United States HL NHLBI NIH HHS; R01 HL173030 United States HL NHLBI NIH HHS; P01HL162607 National Institue of Health; P01 HL162607 United States HL NHLBI NIH HHS; I01 BX003471 United States BX BLRD VA; R01HL17303 National Institue of Health; BX003471 United States VA VA; P01HL162607 United States GF NIH HHS; L30HL154391 National Institue of Health; R01 HL149836 United States HL NHLBI NIH HHS; L30 HL154391 United States HL NHLBI NIH HHS; R01 HL147860 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: ABT-199; apoptosis; idiopathic pulmonary fibrosis; nintedanib; progressive pulmonary fibrosis |
| Substance Nomenclature: | 0 (Indoles) G6HRD2P839 (nintedanib) 0 (Sulfonamides) 0 (Proto-Oncogene Proteins c-bcl-2) 0 (Bridged Bicyclo Compounds, Heterocyclic) N54AIC43PW (venetoclax) 11056-06-7 (Bleomycin) |
| Entry Date(s): | Date Created: 20260506 Date Completed: 20260731 Latest Revision: 20260913 |
| Update Code: | 20260913 |
| PubMed Central ID: | PMC13424840 |
| DOI: | 10.1093/ajrcmb/aanag045 |
| PMID: | 42089301 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1535-4989 |
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| DOI: | 10.1093/ajrcmb/aanag045 |