Progressive transforming growth factor β1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor
Progressive transforming growth factor β1-induced lung fibrosis is blocked by an orally active ALK5 kinase inhibitor
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DOI：
10.1164/rccm.200405-612oc
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发表时间：
2005-04-15
影响因子：
24.7
通讯作者：
Gauldie, J
中科院分区：
文献类型：
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作者：
Bonniaud, P;Margetts, PJ;Gauldie, J
肺纤维化以慢性瘢痕形成和细胞外基质沉积为特征，导致肺功能受损和呼吸衰竭。特发性肺纤维化（IPF）与显著的发病率和死亡率相关，对已知的治疗干预反应较差;目前尚无有效阻断或逆转进行性纤维化的已知药物。已知转化生长因子β（TGF-β）介导细胞外基质基因调节，并且似乎是IPF发生和进展的主要参与者。TGF-β通过激活素受体样激酶（ALK）家族成员介导其生物学效应。我们已经使用了一个进行性TGF-β 1诱导的大鼠肺纤维化的基因转移模型来研究一种新描述的口服活性小分子量药物，该药物是一种有效的选择性ALK 5激酶活性抑制剂，特异性TGF-β受体。我们表明，该药物抑制诱导纤维化时，在开始的纤维化，最重要的是，阻断进行性纤维化时，短暂给予动物建立纤维化。这些数据表明，有希望开发一种有效的IPF治疗干预措施，并且可以通过阻断TGF-β受体活化来抑制慢性进行性纤维化。
Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function and respiratory failure. Idiopathic pulmonary fibrosis (IPF) is associated with pronounced morbidity and mortality and responds poorly to known therapeutic interventions; there are no known drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta (TGF-beta) is known to mediate extracellular matrix gene regulation and appears to be a major player in both the initiation and progression of IPF. TGF-beta mediates its biological effects through members of a family of activin receptor-like kinases (ALK). We have used a gene transfer model of progressive TGF-beta 1-induced pulmonary fibrosis in rats to study a newly described orally active small molecular weight drug that is a potent and selective inhibitor of the kinase activity of ALK5, the specific TGF-beta receptor. We show that the drug inhibits the induction of fibrosis when administered at the time of initiation of fibrogenesis and, most important, blocks progressive fibrosis when administered transiently to animals with established fibrosis. These data show promise of the development of an effective therapeutic intervention for IPF and that inhibition of chronic progressive fibrosis may be achieved by blocking TGF-beta receptor activation.