Sorafenib ameliorates bleomycin-induced pulmonary fibrosis: potential roles in the inhibition of epithelial-mesenchymal transition and fibroblast activation.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a serious progressive and irreversible lung disease with unknown etiology and few treatment options. This disease was once thought to be a chronic inflammatory-driven process, but it is increasingly recognized that the epithelial-mesenchymal transition (EMT) contributes to the cellular origin of fibroblast accumulation in response to injury. During the pathogenesis of pulmonary fibrotic diseases, transforming growth factor-β (TGF-β) signaling is considered a pivotal inducer of EMT and fibroblast activation, and a number of therapeutic interventions that interfere with TGF-β signaling have been developed to reverse established fibrosis. However, efficient and well-tolerated antifibrotic agents are not currently available. Previously, we reported the identification of sorafenib to antagonize TGF-β signaling in mouse hepatocytes in vitro. In this manuscript, we continued to evaluate the antifibrotic effects of sorafenib on bleomycin (BLM)-induced pulmonary fibrosis in mice. We further demonstrated that sorafenib not only profoundly inhibited TGF-β1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and collagen synthesis in fibroblasts. Additionally, we presented in vivo evidence that sorafenib inhibited the symptoms of BLM-mediated EMT and fibroblast activation in mice, warranting the therapeutic potential of this drug for patients with IPF.

• Authors: Y-L Chen, X Zhang, J Bai, L Gai, X-L Ye, L Zhang, Q Xu, Y-X Zhang, L Xu, H-P Li, X Ding
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e665 (Jun 13 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23764846 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Phenylurea Compounds
• Protein Kinase Inhibitors
• Smad Proteins
• Transforming Growth Factor beta1
• Bleomycin
• Niacinamide
• Sorafenib

Topics

• Alveolar Epithelial Cells (drug effects, physiology)
• Animals
• Apoptosis
• Bleomycin
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Extracellular Matrix (metabolism)
• Female
• Fibroblasts (drug effects, physiology)
• HEK293 Cells
• Humans
• Idiopathic Pulmonary Fibrosis (chemically induced, drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• NIH 3T3 Cells
• Niacinamide (analogs & derivatives, pharmacology, therapeutic use)
• Phenylurea Compounds (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Smad Proteins (metabolism)
• Sorafenib
• Transforming Growth Factor beta1 (physiology)