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 in fibrogenesis in vivo. The profibrotic cytokine, transforming growth factor β1 (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. The therapeutic efficiency of Src kinase inhibition in vivo was tested in the bleomycin murine lung fibrosis model. Collagen accumulation, total fibrotic area, and expression of α-smooth muscle actin and ECM proteins were significantly decreased in lungs of AZD0530-treated mice. These results provide evidence for targeting the noncanonical TGF-β signaling pathway involving Src kinase as an effective therapeutic strategy for lung fibrosis.
See article at J Pharmacol Exp Ther 2014, 351:87–95.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics