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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Bleomycin
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Cell Differentiation / drug effects
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Cell Differentiation / genetics
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Cell Proliferation / drug effects
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Collagen Type I / genetics
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Collagen Type I / metabolism
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DNA / metabolism
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Female
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Focal Adhesion Kinase 1 / antagonists & inhibitors*
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Focal Adhesion Kinase 1 / genetics
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Focal Adhesion Kinase 1 / metabolism
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, Inbred C57BL
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Morpholines / pharmacology*
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Myofibroblasts / drug effects
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Myofibroblasts / metabolism
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Phosphorylation / drug effects
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Phosphorylation / genetics
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Pulmonary Fibrosis / chemically induced
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Pulmonary Fibrosis / drug therapy*
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Pulmonary Fibrosis / genetics
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Pulmonary Fibrosis / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Tyrosine / genetics
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Tyrosine / metabolism
Substances
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ACTA2 protein, human
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Actins
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Collagen Type I
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Morpholines
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Platelet-Derived Growth Factor
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Protein Kinase Inhibitors
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TAE226
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Transforming Growth Factor beta
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Bleomycin
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Tyrosine
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Insulin-Like Growth Factor I
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DNA
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Focal Adhesion Kinase 1
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Ptk2 protein, mouse