EXPERIMENTAL LIVER-CIRRHOSIS INDUCED BY ALCOHOL AND IRON
EXPERIMENTAL LIVER-CIRRHOSIS INDUCED BY ALCOHOL AND IRON
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DOI：
10.1172/jci118077
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发表时间：
1995-07-01
影响因子：
15.9
通讯作者：
BRITTENHAM, GM
中科院分区：
文献类型：
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作者：
TSUKAMOTO, H;HORNE, W;BRITTENHAM, GM
为了确定饮食中补充铁是否加剧了酒精性肝纤维化，向大鼠灌胃给予羰基铁(0.25%重量/体积)，其中加入或不加入乙醇，持续16wk。羰基铁对对照组动物的血液酒精浓度、肝脏生化测量或肝脏组织学没有影响。在乙醇喂养的大鼠和对照组中，补充乙醇都使肝脏非血红素铁的平均浓度增加了两到三倍，但仍保持在或接近正常人的范围。如先前所示，单用乙醇灌胃可显著提高肝脏丙二醛(MDA)、肝脏4-羟基壬烯醛(4HNE)和血清转氨酶(ALT、AST)的浓度。在乙醇中添加铁后，平均丙二醛、4HNE、丙氨酸氨基转移酶和谷草转氨酶进一步增加两倍。组织学检查发现，单纯饮酒组有30%的大鼠出现局灶性纤维化。在同时给予酒精和铁的动物中，所有动物都出现了纤维化，60%的动物出现了废弃的中央-中央桥接模式，两只动物(17%)发展为小结节性肝硬化。铁强化的酒精性肝纤维化与肝组织中丙二醛和4HNE加合物表位的强烈和弥漫免疫染色密切相关。此外，在这些动物中，在肝组织和新分离的肝星状细胞(被认为是肝纤维化中细胞外基质的主要来源)中，前胶原α1(I)和转化生长因子β1的mRNA水平都显著增加。在一些动物中，饲料中补充铁的乙醇灌胃加剧了肝细胞的损伤，促进了肝纤维化的形成，并在一些动物中产生了明显的硬化。这些结果为铁和铁催化的氧化应激在酒精性肝病进展中的关键作用提供了证据。
To determine if alcoholic liver fibrogenesis is exacerbated by dietary iron supplementation, carbonyl iron (0.25% wt/vol) was intragastrically infused with or without ethanol to rats for 16 wk. Carbonyl iron had no effect on blood alcohol concentration, hepatic biochemical measurements, or liver histology in control animals. In both ethanol-fed and control rats, the supplementation produced a two- to threefold increase in the mean hepatic non-heme iron concentration but it remained within or near the range found in normal human subjects, As previously shown, the concentrations of liver malondialdehyde (MDA),(1) liver 4-hydroxynonenal (4HNE), and serum aminotransferases (ALT, AST) were significantly elevated by ethanol infusion alone. The addition of iron supplementation to ethanol resulted in a further twofold increment in mean MDA, 4HNE, ALT, and AST. On histological examination, focal fibrosis was found < 30% of the rats fed ethanol alone. In animals given both ethanol and iron, fibrosis was present in all, with a disuse central-central bridging pattern in 60%, and two animals (17%) developed micronodular cirrhosis. The iron-potentiated alcoholic liver fibrogenesis was closely associated with intense and diffuse immunostaining for MDA and 4HNE adduct epitopes in the livers. Furthermore, in these animal, accentuated increases in procollagen alpha 1(I) and TGF beta 1 mRNA levels were found in both liver tissues and freshly isolated hepatic stellate cells, perisinusoidal cells believed to be a major source of extracellular matrices in liver fibrosis, The dietary iron supplementation to intragastric ethanol infusion exacerbates hepatocyte damage, promotes liver fibrogenesis, and produces evident cirrhosis in some animals. These results provide evidence for a critical role of iron and iron-catalyzed oxidant stress in progression of alcoholic liver disease.