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

TLDR

Idiopathic pulmonary fibrosis is a progressive, fatal lung disease of unclear etiology, and anti‑inflammatory therapies have failed, with recent evidence pointing to dysregulated fibroblasts driven by profibrotic cytokines such as TGF‑β and PDGF. This study aimed to determine whether TGF‑β–induced fibrosis is mediated through activation of the Abelson (Abl) tyrosine kinase. The authors examined TGF‑β signaling in fibroblasts, showing that it activates c‑Abl independently of Smad2/3 or PDGFR, and tested the Abl inhibitor imatinib in vitro and in a bleomycin‑induced mouse model of pulmonary fibrosis. They found that c‑Abl drives TGF‑β–induced extracellular‑matrix gene expression, morphological change, and proliferation, and that imatinib blocks these responses and markedly reduces bleomycin‑induced lung fibrosis, indicating Abl family members as therapeutic targets.

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.