title: Therapeutic targeting of SRC kinase in myofibroblast differentiation and pulmonary fibrosis.
abstract: Myofibroblasts are effector cells in fibrotic disorders that synthesize and remodel the extracellular matrix (ECM). This study investigated the role of the Src kinase pathway in myofibroblast activation in vitro and fibrogenesis in vivo. The profibrotic cytokine, transforming growth factor β1 (TGF-β1), induced rapid activation of Src kinase, which led to myofibroblast differentiation of human lung fibroblasts. The Src kinase inhibitor AZD0530 (saracatinib) blocked TGF-β1-induced Src kinase activation in a dose-dependent manner. Inhibition of Src kinase significantly reduced α-smooth muscle actin (α-SMA) expression, a marker of myofibroblast differentiation, in TGF-β1-treated lung fibroblasts. In addition, the induced expression of collagen and fibronectin and three-dimensional collagen gel contraction were also significantly inhibited in AZD0530-treated fibroblasts. The therapeutic efficiency of Src kinase inhibition in vivo was tested in the bleomycin murine lung fibrosis model. Src kinase activation and collagen accumulation were significantly reduced in the lungs of AZD0530-treated mice when compared with controls. Furthermore, the total fibrotic area and expression of α-SMA and ECM proteins were significantly decreased in lungs of AZD0530-treated mice. These results indicate that Src kinase promotes myofibroblast differentiation and activation of lung fibroblasts. Additionally, these studies provide proof-of-concept for targeting the noncanonical TGF-β signaling pathway involving Src kinase as an effective therapeutic strategy for lung fibrosis.
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Meng
authors.initials: M
authors.lastname: Hu
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Pulin
authors.initials: P
authors.lastname: Che
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Xiaosi
authors.initials: X
authors.lastname: Han
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Cai
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Veena
authors.initials: V
authors.lastname: Antony
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Tracy
authors.initials: T
authors.lastname: Luckhardt
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Rui-ming
authors.initials: RM
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Leena P
authors.initials: LP
authors.lastname: Desai
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Reilly
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Thannickal
authors.affiliation: Departments of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine (M.H., G.Q.-C., G.L., V.A., T.L., Y.Z., R.L., L.P.D., P.J.O., V.J.T., Q.D.), Cell, Development, and Integrative Biology (P.C.), Neurology (X.H.), and Pathology (G.P.S.), University of Alabama at Birmingham, Birmingham, Alabama qding@uab.edu.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D011658:Pulmonary Fibrosis / Q000188:drug therapy*; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000199:Actins; D052117:Benzodioxoles; D004791:Enzyme Inhibitors; D011799:Quinazolines; D016212:Transforming Growth Factor beta; D003094:Collagen; C515233:saracatinib; D019061:src-Family Kinases