Centre for Liver Research, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, United Kingdom.
Liver Transpl. 2010 Nov;16(11):1303-13. doi: 10.1002/lt.22157.
Increasing evidence shows that reactive oxygen species (ROS) may be critical mediators of liver damage during the relative hypoxia of ischemia/reperfusion injury (IRI) associated with transplant surgery or of the tissue microenvironment created as a result of chronic hepatic inflammation or infection. Much work has been focused on Kupffer cells or liver resident macrophages with respect to the generation of ROS during IRI. However, little is known about the contribution of endogenous hepatocyte ROS production or its potential impact on the parenchymal cell death associated with IRI and chronic hepatic inflammation. For the first time, we show that human hepatocytes isolated from nondiseased liver tissue and human hepatocytes isolated from diseased liver tissue exhibit marked differences in ROS production in response to hypoxia/reoxygenation (H-R). Furthermore, several different antioxidants are able to abrogate hepatocyte ROS-induced cell death during hypoxia and H-R. These data provide clear evidence that endogenous ROS production by mitochondria and nicotinamide adenine dinucleotide phosphate oxidase drives human hepatocyte apoptosis and necrosis during hypoxia and H-R and may therefore play an important role in any hepatic diseases characterized by a relatively hypoxic liver microenvironment. In conclusion, these data strongly suggest that hepatocytes and hepatocyte-derived ROS are active participants driving hepatic inflammation. These novel findings highlight important functional/metabolic differences between hepatocytes isolated from normal donor livers, hepatocytes isolated from normal resected tissue obtained during surgery for malignant neoplasms, and hepatocytes isolated from livers with end-stage disease. Furthermore, the targeting of hepatocyte ROS generation with antioxidants may offer therapeutic potential for the adjunctive treatment of IRI and chronic inflammatory liver diseases.
越来越多的证据表明，活性氧（ROS）可能是与移植手术相关的缺血/再灌注损伤（IRI）期间相对缺氧或慢性肝炎症或感染导致的组织微环境中肝损伤的关键介质。许多工作都集中在库普弗细胞或肝脏驻留巨噬细胞在IRI 期间产生 ROS 方面。然而，对于内源性肝细胞 ROS 产生的贡献或其对与 IRI 和慢性肝炎症相关的实质细胞死亡的潜在影响知之甚少。我们首次表明，从非病变肝组织中分离的人原代肝细胞和从病变肝组织中分离的人原代肝细胞在对缺氧/复氧（H-R）的反应中表现出明显不同的 ROS 产生。此外，几种不同的抗氧化剂能够在缺氧和 H-R 期间消除肝细胞 ROS 诱导的细胞死亡。这些数据清楚地表明，线粒体和烟酰胺腺嘌呤二核苷酸磷酸氧化酶产生的内源性 ROS 驱动人原代肝细胞在缺氧和 H-R 期间发生细胞凋亡和坏死，因此在任何以相对缺氧的肝脏微环境为特征的肝脏疾病中可能发挥重要作用。总之，这些数据强烈表明肝细胞和肝细胞衍生的 ROS 是驱动肝炎症的活跃参与者。这些新发现突出了从正常供体肝脏分离的肝细胞、从手术切除的正常组织中分离的肝细胞以及从终末期疾病肝脏中分离的肝细胞之间的重要功能/代谢差异。此外，用抗氧化剂靶向肝细胞 ROS 生成可能为 IRI 和慢性炎症性肝病的辅助治疗提供治疗潜力。
