Siegmund Sören V, Brenner David A
Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
Alcohol Clin Exp Res. 2005 Nov;29(11 Suppl):102S-109S. doi: 10.1097/01.alc.0000189275.97419.58.
Alcohol abuse is a main cause of liver fibrosis and cirrhosis in the western world. Although the major mechanisms of fibrogenesis are independent of the origin of liver injury, alcoholic liver fibrosis features distinctive characteristics, including the pronounced inflammatory response of immune cells due to elevated gut-derived endotoxin plasma levels, increased formation of reactive oxygen species (ROS), ethanol-induced pericentral hepatic hypoxia or formation of cell-toxic and pro-fibrogenic ethanol metabolites (e.g., acetaldehyde or lipid oxidation products). These factors are together responsible for increased hepatocellular cell death and activation of hepatic stellate cells (HSCs), the key cell type of liver fibrogenesis. To date, removing the causative agent is the most effective intervention to prevent the manifestation of liver cirrhosis. A novel experimental approach in fibrosis therapy is the selective induction of cell death in HSCs. Substances such as gliotoxin, anandamide or antibody against tissue inhibitor of metalloproteinase (TIMP)-1 can selectively induce cell death in activated HSCs. These new results in basic science are encouraging for the search of new antifibrotic treatment.
在西方世界，酒精滥用是肝纤维化和肝硬化的主要原因。尽管纤维化形成的主要机制与肝损伤的起源无关，但酒精性肝纤维化具有独特的特征，包括由于肠道来源的内毒素血浆水平升高导致免疫细胞明显的炎症反应、活性氧（ROS）形成增加、乙醇诱导的肝小叶中央区缺氧或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。这些因素共同导致肝细胞死亡增加和肝星状细胞（HSCs）活化，肝星状细胞是肝纤维化形成的关键细胞类型。迄今为止，去除致病因素是预防肝硬化表现的最有效干预措施。纤维化治疗中的一种新的实验方法是选择性诱导肝星状细胞死亡。诸如胶质毒素、花生四烯乙醇胺或抗金属蛋白酶组织抑制剂（TIMP）-1抗体等物质可以选择性诱导活化的肝星状细胞死亡。基础科学中的这些新结果为寻找新的抗纤维化治疗方法带来了希望。
