Inhibition of Raf1 ameliorates bleomycin-induced pulmonary fibrosis through attenuation of TGFβ1 signaling

Idiopathic Pulmonary Fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation and differentiation of fibroblasts, leading to abnormal extracellular matrix (ECM) production. Currently, it is still an untreatable disease except lung transplantation. Here, we demonstrate that the Raf1 inhibitor GW5074 ameliorates lung fibrosis in bleomycin-induced pulmonary fibrosis. Post-treatment with GW5074 reduced fibronectin (FN) expression, collagen deposition, and inflammatory cell infiltration in bleomycin-challenged mice, suggesting an anti-fibrotic property of GW5074. To determine the molecular mechanisms by which inhibition of Raf1 ameliorates lung fibrosis, we investigated the role of Raf1 in TGFβ1 signaling in human lung fibroblasts. GW5074 or downregulation of Raf1 by siRNAs significantly attenuated TGFβ1-induduced smooth muscle actin (SMA), FN, and collagen I expression, whereas overexpression of Raf1 promoted the effects of TGFβ1 in lung fibroblasts. Further, we found that Raf1-prom...