Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis
Craig E. Daniels, … , Andrew H. Limper, Edward B. Leof
Craig E. Daniels, … , Andrew H. Limper, Edward B. Leof
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1308-1316. https://doi.org/10.1172/JCI19603.
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Article Nephrology

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

Abstract

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.

Authors

Craig E. Daniels, Mark C. Wilkes, Maryanne Edens, Ted J. Kottom, Stephen J. Murphy, Andrew H. Limper, Edward B. Leof

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Imatinib reduces hydroxyproline content and prevents histopathologic cha...
Imatinib reduces hydroxyproline content and prevents histopathologic changes in BLM-treated lungs. (A) Twenty-eight days after intratracheal instillation of BLM or saline, mice were sacrificed (control, n = 12; BLM, n = 15; BLM plus imatinib, n = 14; imatinib, n = 8). The left lung of each animal was used for hydroxyproline assay as described in Methods and previously (52). *P < 0.05 vs. BLM mice receiving imatinib. There was no significant difference (P > 0.05) among control, BLM plus imatinib, and imatinib groups. (B) Mice were treated as in A. The right lung was sectioned and stained with H&E or Masson’s trichrome to visualize collagen. Representative images are shown at ×10 phase. (C) A morphologic score (44) was assigned in a blinded fashion to H&E-stained samples. Zero indicates no fibrosis, 1 indicates occasional small subpleural foci, 2 indicates interalveolar septal thickening and subpleural foci, and 3 indicates continuous interalveolar and subpleural fibrosis. There was no significant difference among the control, BLM plus imatinib, and imatinib groups. (D) Mice were treated as described for A. Immediately prior to explantation trachea were cannulated and lavaged with a total of 10 ml 0.9 normal saline. The collected fluid was centrifuged, and the cell differential was determined. Gray bars indicate percent macrophages, while red and green reflect polymorphonuclear cells and lymphocytes, respectively. Error bars indicate the SE of measurement between samples within the same group.