Prevention of Drug-Induced Lung Fibrosis via Inhibition of the MRTF/SRF Transcription Pathway
| Autor: | Scott D. Larsen, Megan Varnum, Jack R. Harkema, Kendell M. Pawelec, Bruce Auerbach, Richard R. Neubig |
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| Rok vydání: | 2021 |
| Předmět: |
medicine.diagnostic_test
business.industry Connective tissue Inflammation Pharmacology medicine.disease Bleomycin chemistry.chemical_compound Bronchoalveolar lavage medicine.anatomical_structure chemistry Fibrosis Prednisolone medicine Nintedanib medicine.symptom business Myofibroblast medicine.drug |
| Popis: | Drug-induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality. A number of drugs can cause fibrosis, many of which are used to treat cancer, including chemotherapy agents and immune checkpoint inhibitors. 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 IC50s 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 chemotherapy-induced lung fibrosis. Animals were given intraperitoneal bleomycin for four weeks, and concurrently dosed with CCG-257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti-fibrotic (nintedanib), or 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. Prednisolone led to marked increases in lung fibrosis. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent drug-induced lung fibrosis in a clinically relevant model of drug-induced disease. |
| Databáze: | OpenAIRE |
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