The American journal of pathology
-
Progressive fibrotic diseases involving diverse organ systems are associated with the persistence of fibroblasts/myofibroblasts in injured tissues. Activation of focal adhesion kinase (FAK) and protein kinase B (PKB/Akt) by transforming growth factor-beta1 mediate stable induction of myofibroblast differentiation and survival. In this report, we demonstrate that transforming growth factor-beta1-induced activation of both PKB/Akt and FAK are dose dependently inhibited by the protein kinase inhibitor, AG1879, in cultured human lung fibroblasts. ⋯ The numbers of recruited inflammatory cells were not significantly different between these groups. Bleomycin-AG1879 mice are protected from lung fibrosis as evidenced by histopathology, trichrome staining, and biochemical analysis for collagen. Thus, targeting of prosurvival signaling pathways in fibroblasts/myofibroblasts may provide a novel and effective strategy for anti-fibrotic therapy of treatment-unresponsive fibrotic disorders.