Zhou Zhanxiang, Wang Lipeng, Song Zhenyuan, Lambert Jason C, McClain Craig J, Kang Y James
Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, MDR 525, Louisville, KY, USA.
Am J Pathol. 2003 Sep;163(3):1137-46. doi: 10.1016/s0002-9440(10)63473-6.
Tumor necrosis factor-alpha (TNF-alpha) production is a critical factor in the pathogenesis of alcoholic liver injury. Both oxidative stress and endotoxin have been implicated in the process of alcohol-induced TNF-alpha production. However, a cause-and-effect relationship between these factors has not been fully defined. The present study was undertaken to determine the mediators of acute alcohol-induced TNF-alpha production using a mouse model of acute alcohol hepatotoxicity. Alcohol administration via gavage at a dose of 6 g/kg to 129/Sv mice induced hepatic TNF-alpha production in Kupffer cells as demonstrated by measuring protein levels, immunohistochemical localization, and mRNA expression. Alcohol intoxication caused liver injury in association with increases in plasma endotoxin and hepatic lipid peroxidation. Treatment with an endotoxin neutralizing protein significantly suppressed alcohol-induced elevation of plasma endotoxin, hepatic lipid peroxidation, and inhibited TNF-alpha production. Treatment with antioxidants, N-ACETYL-L-CYSTEINE, or dimethylsulfoxide, failed to attenuate plasma endotoxin elevation, but significantly inhibited alcohol-induced hepatic lipid peroxidation, TNF-alpha production and steatosis. All treatments prevented alcohol-induced necrotic cell death in the liver. This study thus systemically dissected the relationship among plasma endotoxin elevation, hepatic oxidative stress, and TNF-alpha production following acute alcohol administration, and the results demonstrate that oxidative stress mediates endotoxin-induced hepatic TNF-alpha production in acute alcohol intoxication.
肿瘤坏死因子-α（TNF-α）的产生是酒精性肝损伤发病机制中的一个关键因素。氧化应激和内毒素都与酒精诱导的TNF-α产生过程有关。然而，这些因素之间的因果关系尚未完全明确。本研究旨在使用急性酒精性肝毒性小鼠模型来确定急性酒精诱导的TNF-α产生的介质。通过灌胃以6 g/kg的剂量给129/Sv小鼠施用酒精，通过测量蛋白质水平、免疫组织化学定位和mRNA表达证明，诱导了库普弗细胞中肝脏TNF-α的产生。酒精中毒导致肝损伤，同时血浆内毒素和肝脏脂质过氧化增加。用内毒素中和蛋白治疗可显著抑制酒精诱导的血浆内毒素升高、肝脏脂质过氧化，并抑制TNF-α的产生。用抗氧化剂N-乙酰-L-半胱氨酸或二甲基亚砜治疗未能减轻血浆内毒素升高，但显著抑制了酒精诱导的肝脏脂质过氧化、TNF-α产生和脂肪变性。所有治疗均预防了酒精诱导的肝脏坏死性细胞死亡。因此，本研究系统地剖析了急性酒精给药后血浆内毒素升高、肝脏氧化应激和TNF-α产生之间的关系，结果表明氧化应激介导了急性酒精中毒时内毒素诱导的肝脏TNF-α产生。
