[HTML][HTML] Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

CE Daniels, MC Wilkes, M Edens… - The Journal of …, 2004 - Am Soc Clin Investig
CE Daniels, MC Wilkes, M Edens, TJ Kottom, SJ Murphy, AH Limper, EB Leof
The Journal of clinical investigation, 2004Am Soc Clin Investig
Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with
unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-
inflammatory therapy have not proven to be effective. Recent insight suggests that the
pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic
cytokine signaling. TGF-β and PDGF are 2 of the most potent of these cytokines. In the
current study, we investigated the role of TGF-β–induced fibrosis mediated by activation of …
Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-β and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-β–induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-β by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-β–induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.
The Journal of Clinical Investigation