Hepatology：NADPH氧化酶（NOX）抑制疗法治疗肝纤维化

近日，刊登在国际著名杂志Hepatology上的一篇研究报告报道了肝纤维化的一种新的NADPH氧化酶（NOX）抑制疗法，肝纤维化是一种慢性肝脏疾病，常常导致肝功能的缺失。许多研究阐释了在实验动物中肝纤维化的相关研究，但是目前并没有有效的治疗此疾病的方法。研究者David表示，他们这项新的研究方法揭示了NOX在疾病治疗上扮演的角色。

大多数的慢性肝脏疾病都和进行中的纤维化有关，另外来自组织中的活性氧ROS可以导致肝脏组织的异常修复。因为酒精或者感染引发的肝脏损伤时，造血干细胞会被激活变成成肌纤维细胞，这种细胞在机体伤口愈合和免疫效应上扮演着重要角色。这个过程由涉及NOX的胞内信号通道所引发，可以导致结疤的形成，并且最终引发器官功能的损失。

通过抑制NOX，研究者表示成肌纤维细胞的激活和机体的免疫效应会被打断，最终抑制纤维化或者阻止纤维化进程。研究者评估了了这种新型疗法GTK137831（NOX抑制疗法）的可行性，通过在小鼠模型中进行实验，研究者发现使用NOX抑制疗法可以抑制ROS的产生，并且可以有效抑制纤维化基因的产生。这项研究将重点突出新型NOX抑制疗法的潜在效用，后期还需要深入的临床试验验证其效果。

编译自：Drug Successfully Halts Fibrosis in Animal Model of Liver Disease

doi:10.1002/hep.25938
PMC:
PMID:

Nicotinamide adenine dinucleotide phosphate oxidase (nox) in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent

Tomonori Aoyama1,2, Yong-Han Paik3, Sumio Watanabe2, Benoît Laleu4, Francesca Gaggini4, Laetitia Fioraso-Cartier4, Sophie Molango4, Freddy Heitz4, Cédric Merlot4, Cédric Szyndralewiez4, Patrick Page4, David A.Brenner1,†,*

Background & Aims: NADPH oxidase (NOX) generates reactive oxygen species (ROS) in hepatic stellate cells (HSCs) during liver fibrosis. In response to fibrogenic agonists, such as angiotensin II (Ang II), the NOX1 components form an active complex including Rac1. Superoxide dismutase 1 (SOD1) interacts with the NOX-Rac1 complex to stimulate NOX activity. NOX4 is also induced in activated HSCs/myofibroblast by increased gene expression. Here, we investigate the role of an enhanced activity SOD1 G37R mutation (SODmu) and the effects of GKT137831, a dual NOX1/4 inhibitor, on HSCs and liver fibrosis. Methods: To induce liver fibrosis, wild-type (WT) and SOD1mu mice were treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). Then, to address the role of NOX-SOD1-mediated ROS production in HSC activation and liver fibrosis, mice were treated with a NOX1/4 inhibitor. Fibrosis and ROS generation was assessed by histology and measurement of TBARS and NOX related genes. Primary cultured HSCs isolated from WT, SODmu, and NOX1 knock-out (KO) mice were assessed for ROS production, Rac1 activity, and NOX gene expression. Results: Liver fibrosis was increased in SOD1mu mice, and ROS production and Rac1 activity were increased in SOD1mu HSCs. The NOX1/4 inhibitor GKT137831 attenuated liver fibrosis and ROS production in both SOD1mu and WT mice as well as mRNA expression of fibrotic and NOX genes. Treatment with GKT137831 suppressed ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT HSCs. Both Ang II and TGFb upregulated NOX4, but AngII required NOX1. Conclusions: SOD1mu induces excessive NOX1 activation through Rac1 in HSCs, causing enhanced NOX4 upregulation, ROS generation, and liver fibrosis. Treatment targeting NOX1/4 may be a new therapy for liver fibrosis. (Hepatology 2011.)