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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis

Meng Hu, Pulin Che, Xiaosi Han, Guo-Qiang Cai, Gang Liu, Veena Antony, Tracy Luckhardt, Gene P. Siegal, Yong Zhou, Rui-ming Liu, Leena P. Desai, Philip J. O’Reilly, Victor J. Thannickal and Qiang Ding
Journal of Pharmacology and Experimental Therapeutics October 2014, 351 (1) 87-95; DOI: https://doi.org/10.1124/jpet.114.216044
Meng Hu
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
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Pulin Che
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
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Xiaosi Han
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
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Guo-Qiang Cai
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
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Gang Liu
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
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Veena Antony
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
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Tracy Luckhardt
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
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Gene P. Siegal
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
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Yong Zhou
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
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Rui-ming Liu
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
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Leena P. Desai
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
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Philip J. O’Reilly
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
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Victor J. Thannickal
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
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Qiang Ding
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
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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.

Footnotes

    • Received April 28, 2014.
    • Accepted July 18, 2014.
  • M.H. and P.C. contributed equally to this work.

  • This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-HL085324 (to Q.D.), R01-HL105473 (to G.L.), and P01-HL114470 (to V.J.T.)]. The authors declare no conflicts of interest.

  • dx.doi.org/10.1124/jpet.114.216044.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 1
1 Oct 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Targeting Src Kinase in Lung Fibrosis

Meng Hu, Pulin Che, Xiaosi Han, Guo-Qiang Cai, Gang Liu, Veena Antony, Tracy Luckhardt, Gene P. Siegal, Yong Zhou, Rui-ming Liu, Leena P. Desai, Philip J. O’Reilly, Victor J. Thannickal and Qiang Ding
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 87-95; DOI: https://doi.org/10.1124/jpet.114.216044

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Targeting Src Kinase in Lung Fibrosis

Meng Hu, Pulin Che, Xiaosi Han, Guo-Qiang Cai, Gang Liu, Veena Antony, Tracy Luckhardt, Gene P. Siegal, Yong Zhou, Rui-ming Liu, Leena P. Desai, Philip J. O’Reilly, Victor J. Thannickal and Qiang Ding
Journal of Pharmacology and Experimental Therapeutics October 1, 2014, 351 (1) 87-95; DOI: https://doi.org/10.1124/jpet.114.216044
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