Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis.
Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis.
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DOI：
10.1172/jci19603
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发表时间：
2004-11
期刊：
影响因子：
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通讯作者：
C. Daniels;M. Wilkes;M. Edens;T. Kottom;S. Murphy;A. Limper;E. Leof
中科院分区：
文献类型：
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作者：
C. Daniels;M. Wilkes;M. Edens;T. Kottom;S. Murphy;A. Limper;E. Leof
特发性肺纤维化是一种病因不明的进行性、致死性肺纤维化疾病。先前治疗特发性肺纤维化的努力集中在抗炎治疗上，但尚未证明有效。最近的见解表明，发病机制是通过由促纤维化细胞因子信号传导驱动的失调的成纤维细胞灶介导的。TGF-β和PDGF是这些细胞因子中最有效的两种。在目前的研究中，我们调查的作用，TGF-β诱导的纤维化介导的激活Abelson（Abl）酪氨酸激酶。我们的数据表明，成纤维细胞通过刺激c-Abl激酶活性对TGF-β产生反应，而不依赖于Smad 2/3磷酸化或PDGFR激活。此外，伊马替尼抑制c-Abl阻止TGF-β诱导的ECM基因表达、形态转化和细胞增殖，与Smad信号传导的任何影响无关。此外，使用博莱霉素诱导的肺纤维化的小鼠模型，我们发现伊马替尼对肺纤维化有显著的抑制作用。因此，Abl家族成员代表调节促纤维化细胞因子信号传导的共同靶标。
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-beta and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-beta-induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-beta by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-beta-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.