de Gouville Anne-Charlotte, Huet Stephane
Biology Department, Glaxo-SmithKline Pharmaceuticals, Les Ulis, France.
Drug News Perspect. 2006 Mar;19(2):85-90. doi: 10.1358/dnp.2006.19.2.977444.
Liver fibrosis is the result of an unbalanced wound healing response to a chronic hepatic injury. Transforming growth factor-beta (TGF-beta) plays a major role in this process via the activation of hepatic stellate cells. Various approaches have been tested in animal models of fibrosis to block the effects of TGF-beta, including antibodies and soluble receptors. Here, we discuss the potential use of TGF-beta signaling inhibitors, acting at the TGF-beta type I receptor kinase (ALK5) level, as a possible therapy for liver fibrosis. Thus far, there is only one ALK5 inhibitor (GW6604) for which activity in models of liver fibrosis has been described, showing clear antifibrotic effects resulting in liver function improvement. However, due to the pleiotropic effects of TGF-beta, the beneficial antifibrotic effects of ALK5 inhibition should be carefully balanced against the potential risk of unwanted effects stemming from chronic treatment.
肝纤维化是对慢性肝损伤的伤口愈合反应失衡的结果。转化生长因子-β（TGF-β）通过激活肝星状细胞在这一过程中起主要作用。在肝纤维化动物模型中已经测试了各种方法来阻断TGF-β的作用，包括抗体和可溶性受体。在这里，我们讨论了作用于TGF-βⅠ型受体激酶（ALK5）水平的TGF-β信号抑制剂作为肝纤维化可能治疗方法的潜在用途。到目前为止，只有一种ALK5抑制剂（GW6604），其在肝纤维化模型中的活性已被描述，显示出明显的抗纤维化作用，从而改善肝功能。然而，由于TGF-β的多效性，ALK5抑制的有益抗纤维化作用应与长期治疗产生的潜在不良影响风险仔细权衡。
