title: 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.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PRC. chenyl@sibcb.ac.cn
authors.forename: Y-L
authors.initials: YL
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J
authors.initials: J
authors.lastname: Bai
authors.forename: L
authors.initials: L
authors.lastname: Gai
authors.forename: X-L
authors.initials: XL
authors.lastname: Ye
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.forename: Y-X
authors.initials: YX
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: H-P
authors.initials: HP
authors.lastname: Li
authors.forename: X
authors.initials: X
authors.lastname: Ding
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D009536:Niacinamide; D000077157:Sorafenib