Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, 66160, USA.
J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:173-9. doi: 10.1111/j.1440-1746.2010.06592.x.
Liver cell death induced by stresses such as ischemia-reperfusion, cholestasis and drug toxicity can trigger a sterile inflammatory response with activation of innate immune cells through release of damage-associated molecular patterns (DAMPs). A similar inflammatory response can be induced by pathogen-associated molecular patterns (PAMPs) such as endotoxin. Both DAMPs and PAMPs activate through toll-like receptors the resident macrophages (Kupffer cells) and recruit activated neutrophils and monocytes into the liver. Central to this inflammatory response is promotion of reactive oxygen species (ROS) formation by these phagocytes. ROS are the principal toxic mediators by which inflammatory cells kill their targets, e.g. bacteria during host defense but also hepatocytes and other liver cells. The mechanism of ROS-induced cell killing during inflammation involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to oncotic necrosis and less apoptosis. The additional release of cell contents amplifies the inflammatory injury. However, an inflammatory oxidant stress insufficient to directly cause cell damage can induce transcription of stress defence genes including antioxidant genes. This preconditioning effect of ROS enhances the resistance against future inflammatory oxidant stress and promotes the initiation of tissue repair processes. Despite the substantial progress in our understanding of mechanisms of inflammatory liver injury during the last decade, more research is necessary to better understand the role of ROS in acute liver inflammation and to develop clinically applicable therapeutic strategies that selectively target the detrimental effects of oxidant stress without compromising the vital function of ROS in host defense.
肝实质细胞死亡可由缺血再灌注、胆汁淤积和药物毒性等多种应激因素诱导，可通过释放损伤相关分子模式（DAMPs）激活固有免疫细胞，引起非感染性炎症反应。病原体相关分子模式（PAMPs）如内毒素也可引起类似的炎症反应。DAMPs 和 PAMPs 通过 toll 样受体激活驻留巨噬细胞（枯否细胞），并招募激活的中性粒细胞和单核细胞进入肝脏。这种炎症反应的核心是促进这些吞噬细胞形成活性氧（ROS）。ROS 是炎症细胞杀死其靶标的主要毒性介质，例如在宿主防御过程中杀死细菌，但也可杀死肝细胞和其他肝脏细胞。ROS 诱导炎症期间细胞杀伤的机制涉及通过肝细胞内的氧化应激促进线粒体功能障碍，主要导致胀亡坏死，凋亡较少。细胞内容物的额外释放放大了炎症损伤。然而，ROS 引起的炎症氧化应激不足以直接导致细胞损伤时，可诱导应激防御基因的转录，包括抗氧化基因。ROS 的这种预处理作用增强了对未来炎症氧化应激的抵抗力，并促进组织修复过程的启动。尽管在过去十年中我们对炎症性肝损伤的机制有了更深入的了解，但仍需要更多的研究来更好地理解 ROS 在急性肝炎症中的作用，并开发出临床上可应用的治疗策略，这些策略选择性地靶向氧化应激的有害影响，而不损害 ROS 在宿主防御中的重要功能。
