Mandrekar Pranoti
Liver Center, Department of Medicine, University of Massachusetts Medical School, LRB 213, 364 Plantation Street, Worcester, MA 01605-2324, USA.
World J Gastroenterol. 2007 Oct 7;13(37):4979-85. doi: 10.3748/wjg.v13.i37.4979.
Alcoholic liver injury comprises of interactions of various intracellular signaling events in the liver. Innate immune responses in the resident Kupffer cells of the liver, oxidative stress-induced activation of hepatocytes, fibrotic events in liver stellate cells and activation of liver sinusoidal endothelial cells all contribute to alcoholic liver injury. The signaling mechanisms associated with alcoholic liver injury vary based on the cell type involved and the extent of alcohol consumption. In this review we will elucidate the oxidative stress and signaling pathways affected by alcohol in hepatocytes and Kupffer cells in the liver by alcohol. The toll-like receptors and their down-stream signaling events that play an important role in alcohol-induced inflammation will be discussed. Alcohol-induced alterations of various intracellular transcription factors such as NFkappaB, PPARs and AP-1, as well as MAPK kinases in hepatocytes and macrophages leading to induction of target genes that contribute to liver injury will be reviewed. Finally, we will discuss the significance of heat shock proteins as chaperones and their functional regulation in the liver that could provide new mechanistic insights into the contributions of stress-induced signaling mechanisms in alcoholic liver injury.
酒精性肝损伤包括肝脏中各种细胞内信号事件的相互作用。肝脏中常驻库普弗细胞的固有免疫反应、氧化应激诱导的肝细胞活化、肝星状细胞的纤维化事件以及肝窦内皮细胞的活化均导致酒精性肝损伤。与酒精性肝损伤相关的信号机制因所涉及的细胞类型和酒精摄入量的不同而有所差异。在本综述中，我们将阐明酒精对肝脏中肝细胞和库普弗细胞的氧化应激及信号通路的影响。将讨论在酒精诱导的炎症中起重要作用的Toll样受体及其下游信号事件。还将综述酒精诱导的肝细胞和巨噬细胞中各种细胞内转录因子（如核因子κB、过氧化物酶体增殖物激活受体和激活蛋白-1）以及丝裂原活化蛋白激酶激酶的改变，这些改变导致有助于肝损伤的靶基因的诱导。最后，我们将讨论热休克蛋白作为伴侣蛋白的意义及其在肝脏中的功能调节，这可能为应激诱导的信号机制在酒精性肝损伤中的作用提供新的机制性见解。
