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Prevention of bleomycin-induced lung fibrosis via inhibition of the MRTF/SRF transcription pathway.
Pawelec, Kendell M; Varnum, Megan; Harkema, Jack R; Auerbach, Bruce; Larsen, Scott D; Neubig, Richard R.
Affiliation
  • Pawelec KM; FibrosIX, East Lansing, Michigan, USA.
  • Varnum M; FibrosIX, East Lansing, Michigan, USA.
  • Harkema JR; BBC Entrepreneurial Training and Consulting, Chelsea, Michigan, USA.
  • Auerbach B; Department of Pathology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA.
  • Larsen SD; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA.
  • Neubig RR; Office of Technology Transfer, University of Michigan, Ann Arbor, Michigan, USA.
Pharmacol Res Perspect ; 10(6): e01028, 2022 12.
Article in En | MEDLINE | ID: mdl-36426895
Bleomycin-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality in chemotherapy patients. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG-257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50 s of 4 and 15 µM, respectively. The ability of CCG-257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of bleomycin-induced lung fibrosis. Animals were given intraperitoneal bleomycin for 4 weeks and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib) or the clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG-257081 gained weight vs. vehicle-treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG-257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG-257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor-1 (PAI-1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. In contrast, prednisolone led to marked increases in lung fibrosis by all metrics. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent bleomycin-induced lung fibrosis in a clinically relevant model of the disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pulmonary Fibrosis / Bleomycin Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Pharmacol Res Perspect Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pulmonary Fibrosis / Bleomycin Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Pharmacol Res Perspect Year: 2022 Document type: Article Affiliation country: United States Country of publication: United States