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

Abstract

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.

Glaucoma: Novel antifibrotic therapeutics for the trabecular meshwork

“…Serum response factor/myocardin-related transcription factor (SRF/MRTF) complex has been shown to be responsible for pathological fibrosis in many organs, such as the eye ( Tagalakis et al, 2018 ), colon ( Johnson et al, 2014 ), kidney ( Miranda et al, 2021 ) and lung ( Pawelec et al, 2022 ). CCG-203971 is a novel inhibitor of the SRF/MRTF complex and can work as potential antifibrotic therapeutics to prevent scar tissue formation in rabbit eyes after glaucoma filtration surgery ( Yu-Wai-Man et al, 2017 ).…”

Inhaled Lipid Nanoparticles Alleviate Established Pulmonary Fibrosis

“…Pulmonary fibrosis, a condition of the lung with excessive scarring, is a kind of chronic, progressive, and ultimately fatal interstitial lung disease that affects >5 million people worldwide. [1,2] Severe infection, [3] chemotherapy, [4] radiotherapy, [5] environmental exposure, [6] or unknown etiologies [7] are able to cause pulmonary fibrosis. According to clinical reports, pulmonary fibrosis is an important clinical manifestation and a common sequela of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.…”