title: Antifibrotic effects of focal adhesion kinase inhibitor in bleomycin-induced pulmonary fibrosis in mice.
abstract: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase involved in various biological functions, including cell survival, proliferation, migration, and adhesion. FAK is an essential factor for transforming growth factor β to induce myofibroblast differentiation. In the present study, we investigated whether the targeted inhibition of FAK by using a specific inhibitor, TAE226, has the potential to regulate pulmonary fibrosis. TAE226 showed inhibitory activity of autophosphorylation of FAK at tyrosine 397 in lung fibroblasts. The addition of TAE226 inhibited the proliferation of lung fibroblasts in response to various growth factors, including platelet-derived growth factor and insulin-like growth factor I, in vitro. TAE226 strongly suppressed the production of type I collagen by lung fibroblasts. Furthermore, treatment of fibroblasts with TAE226 reduced the expression of α-smooth muscle actin induced by transforming growth factor β, indicating the inhibition of differentiation of fibroblasts to myofibroblasts. Administration of TAE226 ameliorated the pulmonary fibrosis induced by bleomycin in mice even when used late in the treatment. The number of proliferating mesenchymal cells was reduced in the lungs of TAE226-treated mice. These data suggest that FAK signal plays a significant role in the progression of pulmonary fibrosis and that it can become a promising target for therapeutic approaches to pulmonary fibrosis.
authors: 1 Department of Respiratory Medicine and Rheumatology and.
authors: Katsuhiro
authors: K
authors: Kinoshita
authors: Yoshinori
authors: Y
authors: Aono
authors: Momoyo
authors: M
authors: Azuma
authors: Jun
authors: J
authors: Kishi
authors: Akio
authors: A
authors: Takezaki
authors: Masami
authors: M
authors: Kishi
authors: Hideki
authors: H
authors: Makino
authors: Hiroyasu
authors: H
authors: Okazaki
authors: Hisanori
authors: H
authors: Uehara
authors: Keisuke
authors: K
authors: Izumi
authors: Saburo
authors: S
authors: Sone
authors: Yasuhiko
authors: Y
authors: Nishioka
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology*; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D024042:Collagen Type I; D009025:Morpholines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; C524632:TAE226; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D004247:DNA; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse