Prevention of bleomycin-induced lung fibrosis via inhibition of the MRTF/SRF transcription pathway.

Autor: Pawelec KM; FibrosIX, East Lansing, Michigan, USA., Varnum M; FibrosIX, East Lansing, Michigan, USA.; BBC Entrepreneurial Training and Consulting, Chelsea, Michigan, USA., Harkema JR; Department of Pathology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan, USA.; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA., Auerbach B; Office of Technology Transfer, University of Michigan, Ann Arbor, Michigan, USA., Larsen SD; FibrosIX, East Lansing, Michigan, USA.; Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA., Neubig RR; FibrosIX, East Lansing, Michigan, USA.; Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan, USA.
Jazyk: angličtina
Zdroj: Pharmacology research & perspectives [Pharmacol Res Perspect] 2022 Dec; Vol. 10 (6), pp. e01028.
DOI: 10.1002/prp2.1028
Abstrakt: 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 IC 50 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.
(© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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