Siegmund Soren V, Dooley Steven, Brenner David A
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Dig Dis. 2005;23(3-4):264-74. doi: 10.1159/000090174.
Alcohol abuse is a major cause of liver fibrosis and cirrhosis in developed countries. Before alcoholic liver fibrosis becomes evident, the liver undergoes several stages of alcoholic liver disease including steatosis and steatohepatitis. Although the main mechanisms of fibrogenesis are independent of the etiology of liver injury, alcoholic liver fibrosis is distinctively characterized by a pronounced inflammatory response due to elevated gut-derived endotoxin plasma levels, an augmented generation of oxidative stress with pericentral hepatic hypoxia and the formation of cell-toxic and profibrogenic ethanol metabolites (e.g. acetaldehyde or lipid oxidation products). These factors, based on a complex network of cytokine actions, together result in increased hepatocellular damage and activation of hepatic stellate cells, the key cell type of liver fibrogenesis. Although to date removal of the causative agent, i.e. alcohol, still represents the most effective intervention to prevent the manifestation of alcoholic liver disease, sophisticated molecular approaches are underway, aiming to specifically blunt profibrogenic signaling pathways in liver cells or specifically induce cell death in activated hepatic stellate cells to decrease the scarring of the liver.
在发达国家，酒精滥用是肝纤维化和肝硬化的主要原因。在酒精性肝纤维化变得明显之前，肝脏会经历酒精性肝病的几个阶段，包括脂肪变性和脂肪性肝炎。尽管纤维化形成的主要机制与肝损伤的病因无关，但酒精性肝纤维化的显著特征是肠道来源的内毒素血浆水平升高导致明显的炎症反应、肝小叶中央周围缺氧导致氧化应激增加以及细胞毒性和促纤维化乙醇代谢产物（如乙醛或脂质氧化产物）的形成。基于细胞因子作用的复杂网络，这些因素共同导致肝细胞损伤增加和肝星状细胞活化，肝星状细胞是肝纤维化形成的关键细胞类型。尽管迄今为止，去除病因即酒精仍然是预防酒精性肝病表现的最有效干预措施，但复杂的分子方法正在进行中，旨在特异性地抑制肝细胞中的促纤维化信号通路或特异性地诱导活化的肝星状细胞死亡，以减少肝脏的瘢痕形成。
