Loguercio Carmela, Federico Alessandro
Gastroenterology School, 2nd University of Naples, and Inter-University Research Center of Alimentary Intake, Nutrition and Digestive Tract (CIRANAD), Naples, Italy.
Free Radic Biol Med. 2003 Jan 1;34(1):1-10. doi: 10.1016/s0891-5849(02)01167-x.
Liver damage ranges from acute hepatitis to hepatocellular carcinoma, through apoptosis, necrosis, inflammation, immune response, fibrosis, ischemia, altered gene expression and regeneration, all processes that involve hepatocyte, Kupffer, stellate, and endothelial cells. Reactive oxygen and nitrogen species (ROS, RNS) play a crucial role in the induction and in the progression of liver disease, independently from its etiology. They are involved in the transcription and activation of a large series of cytokines and growth factors that, in turn, can contribute to further production of ROS and RNS. The main sources of free radicals are represented by hepatocyte mitochondria and cytochrome p450 enzymes, by endotoxin-activated macrophages (Kupffer cells), and by neutrophils. The consequent alteration of cellular redox state is potentiated by the correlated decrease of antioxidant and energetic reserves. Indices of free radical-mediated damage, such as the increase of malondialdehyde, 4-hydroxynonenal, protein-adducts, peroxynitrite, nitrotyrosine, etc., and/or decrease of glutathione, vitamin E, vitamin C, selenium, etc., have been documented in patients with viral or alcoholic liver disease. These markers may contribute to the monitoring the degree of liver damage, the response to antiviral therapies and to the design of new therapeutic strategies. In fact, increasing attention is now paid to a possible "redox gene therapy." By enhancing the antioxidant ability of hepatocytes, through transgene vectors, one could counteract oxidative/nitrosative stress and, in this way, contribute to blocking the progression of liver disease.
肝损伤范围从急性肝炎到肝细胞癌，涉及凋亡、坏死、炎症、免疫反应、纤维化、缺血、基因表达改变和再生等过程，所有这些过程都涉及肝细胞、库普弗细胞、星状细胞和内皮细胞。活性氧和氮物质（ROS，RNS）在肝病的诱发和进展中起着关键作用，与病因无关。它们参与一系列细胞因子和生长因子的转录和激活，而这些细胞因子和生长因子反过来又会促进ROS和RNS的进一步产生。自由基的主要来源是肝细胞线粒体和细胞色素p450酶、内毒素激活的巨噬细胞（库普弗细胞）和中性粒细胞。抗氧化剂和能量储备的相关减少会加剧由此导致的细胞氧化还原状态改变。在病毒性或酒精性肝病患者中，已记录到自由基介导损伤的指标，如丙二醛、4-羟基壬烯醛、蛋白质加合物、过氧亚硝酸盐、硝基酪氨酸等增加，和/或谷胱甘肽、维生素E、维生素C、硒等减少。这些标志物可能有助于监测肝损伤程度、对抗病毒治疗的反应以及新治疗策略的设计。事实上，目前人们越来越关注一种可能的“氧化还原基因疗法”。通过转基因载体增强肝细胞的抗氧化能力，可以对抗氧化/亚硝化应激，从而有助于阻止肝病的进展。
