TY - JOUR T1 - Therapeutic Targeting of Src Kinase in Myofibroblast Differentiation and Pulmonary Fibrosis JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.114.216044 SP - jpet.114.216044 AU - Meng Hu AU - Pulin Che AU - Xiaosi Han AU - Guo-Qiang Cai AU - Gang Liu AU - Veena Antony AU - Tracy Luckhardt AU - Gene P. Siegal AU - Yong Zhou AU - Rui-ming Liu AU - Leena P. Desai AU - Philip J. O'Reilly AU - Victor J. Thannickal AU - Qiang Ding Y1 - 2014/01/01 UR - http://jpet.aspetjournals.org/content/early/2014/07/21/jpet.114.216044.abstract N2 - Myofibroblasts are effector cells in fibrotic disorders by synthesizing and remodeling the extracellular matrix (ECM). This study investigated the role of the Src kinase pathway in myofibroblast activation in vitro and fibrogenesis in vivo. The pro-fibrotic cytokine, transforming growth factor beta-1 (TGF-β1), induced rapid activation of Src kinase that leads 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 alpha-smooth muscle actin (α-SMA) expression, a marker of myofibroblast differentiation, in TGF-β1-treated lung fibroblasts. In addition, induced expression of collagen and fibronectin, and 3D-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 to controls. Furthermore, 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 non-canonical TGF-β signaling pathway involving Src kinase as an effective therapeutic strategy for lung fibrosis. ER -