PLoS ONE：抑制NOX4酶治疗肝纤维化

2012年11月7日 --近日，Bellvitge生物医学研究所研究人员完成的一项研究证实抑制NADPH氧化酶NOX4可以防止肝纤维化。相关研究论文发表在PLoS One杂志上。

研究人员研究了细胞因子转化生长因子-β（TGF-β）在肝脏病理过程中的功能。在纤维化过程中，TGF-β的水平增加，并伴随肝细胞死亡。TGF-β是一个复杂的细胞因子，在肿瘤形成的早期阶段，TGF-β是一个肿瘤抑制基因。

这项研究的目的是分析TGF-β信号途径可能是纤维化发生、细胞的活化和细胞外基质的生产和肝细胞死亡过程的关键通路。

早期研究已经证明，在体外和体内，抑制TGF-β将可能减少纤维化。然而，TGF-β是一种肿瘤抑制基因。抗TGF-β治疗肝纤维化患者是一个危险因素，因为这抑制了潜在的肿瘤抑制基因，在纤维化过程中，可能会诱发慢性肝损害和肝癌。

参与TGF-β信号通路的氧化酶NOX4无论是在体内还是在体外，都在纤维化中起着重要的作用。在纤维化实验模型小鼠中，抑制NOX4既能防止激活细胞外基质产生细胞和肝细胞死亡。研究还表明丙型肝炎病毒感染引起的肝纤维化患者在不同阶段，NOX4的水平是非常高的。目前已经开发出一些NOX4抑制剂药物，因此该研究证明了其临床应用前景，并揭示了它们是如何发挥作用来治疗肝纤维化患者的。

与肝纤维化相关的拓展阅读：

• Clin Infect Dis：血清标志物FIB-4或可用于慢性丙肝纤维化分期
• EJGH：7种非侵入性肝纤维化分期模型有效性评估
• 肝纤维化的诊断与治疗进展
• JAMA：感染HIV/HCV患者肝纤维化分期与ESLD及HCC等综合结果有关
• Hepatology：NADPH氧化酶（NOX）抑制疗法治疗肝纤维化 更多信息请点击：有关肝纤维化更多资讯

NADPH Oxidase NOX4 Mediates Stellate Cell Activation and Hepatocyte Cell Death during Liver Fibrosis Development.

A role for the NADPH oxidases NOX1 and NOX2 in liver fibrosis has been proposed, but the implication of NOX4 is poorly understood yet. The aim of this work was to study the functional role of NOX4 in different cell populations implicated in liver fibrosis: hepatic stellate cells (HSC), myofibroblats (MFBs) and hepatocytes. Two different mice models that develop spontaneous fibrosis (Mdr2-/-/p19ARF-/-, Stat3Δhc/Mdr2-/-) and a model of experimental induced fibrosis (CCl4) were used. In addition, gene expression in biopsies from chronic hepatitis C virus (HCV) patients or non-fibrotic liver samples was analyzed. Results have indicated that NOX4 expression was increased in the livers of all animal models, concomitantly with fibrosis development and TGF-β pathway activation. In vitro TGF-β-treated HSC increased NOX4 expression correlating with transdifferentiation to MFBs. Knockdown experiments revealed that NOX4 downstream TGF-β is necessary for HSC activation as well as for the maintenance of the MFB phenotype. NOX4 was not necessary for TGF-β-induced epithelial-mesenchymal transition (EMT), but was required for TGF-β-induced apoptosis in hepatocytes. Finally, NOX4 expression was elevated in patients with hepatitis C virus (HCV)-derived fibrosis, increasing along the fibrosis degree. In summary, fibrosis progression both in vitro and in vivo (animal models and patients) is accompanied by increased NOX4 expression, which mediates acquisition and maintenance of the MFB phenotype, as well as TGF-β-induced death of hepatocytes.