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Inhibition of Raf1 Ameliorates Bleomycin-Induced Pulmonary Fibrosis Through Attenuation of TGF-β1 Signaling

Inhibition of Raf1 Ameliorates Bleomycin-Induced Pulmonary Fibrosis Through Attenuation of TGF-β1 Signaling

Shuang Li, Jia Liu, Jiangning Tan, Lian Li, Mary J Kaltreider, Jing Zhao, Daniel J Kass, Dong Shang, Yutong Zhao

Am J Physiol Lung Cell Mol Physiol. 2018 Aug 1;315(2):L241-L247.

PMID: 29722566

Abstract:

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation and differentiation of fibroblasts, leading to abnormal extracellular matrix production. Currently, it is still an untreatable disease (except for lung transplantation). Here, we demonstrate that the Raf1 inhibitor GW5074 ameliorates lung fibrosis in bleomycin-induced pulmonary fibrosis. Posttreatment with GW5074 reduced fibronectin (FN) expression, collagen deposition, and inflammatory cell infiltration in bleomycin-challenged mice, suggesting an antifibrotic property of GW5074. To determine the molecular mechanisms by which inhibition of Raf1 ameliorates lung fibrosis, we investigated the role of Raf1 in TGF-β1 signaling in human lung fibroblasts. GW5074 or downregulation of Raf1 by siRNAs significantly attenuated TGF-β1-induced smooth muscle actin, FN, and collagen I expression, whereas overexpression of Raf1 promoted the effects of TGF-β1 in lung fibroblasts. Furthermore, we found that Raf1-promoted TGF-β1 signaling was through the Raf1/ERK/Smad pathway and contributed to the cell proliferation and migration in human lung fibroblasts. This study provides preclinical and mechanistic evidence for development of Raf1 inhibitors as potential antifibrotic drugs for the treatment of IPF.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP220904836-A	GW5074		220904-83-6	Price

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