Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice
Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice
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DOI：
10.1124/jpet.102.047852
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发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Kang, YJ
中科院分区：
文献类型：
--
作者：
Lambert, JC;Zhou, ZX;Kang, YJ
急性乙醇暴露可导致实验动物肝损伤，越来越多的证据表明，其发病机制的一个主要因素是内毒素血症，这是由于酒精刺激下肠道通透性增加导致细菌内毒素从小肠渗漏造成的。本研究旨在探讨锌预处理是否能通过预防肠通透性改变来抑制急性乙醇性肝损伤。雄性129 Sv(PC)J小鼠在急性乙醇攻击前，以每公斤5毫克锌离子的剂量灌胃3次ZnSO4，每次剂量为6克/公斤乙醇。锌处理没有改变血清酒精浓度的升高。急性乙醇暴露导致血清丙氨酸转氨酶水平升高，以及脂肪肝和肝脏退行性坏死灶，分别通过生化试验和组织化学分析确定。酶联免疫吸附法检测肝脏肿瘤坏死因子- α (tnf - α)水平显著升高。这些病理效应与血清内毒素水平升高密切相关。重要的是，急性乙醇处理对小肠造成了明显的损伤，这是由肠切片形态学分析和通透性试验确定的。这些酒精引起的肝脏病理改变和tnf - α升高在锌预处理的动物中被显著抑制。锌对酒精性肝损伤和炎症激活的抑制作用与锌抑制酒精性肠通透性改变有关。这些结果表明，锌预防肠通透性增加在抑制小鼠急性乙醇性肝损伤中起重要作用。
Acute ethanol exposure causes liver injury in experimental animals, and accumulating evidence suggests that a major responsible factor for the pathogenesis is endotoxemia, which results from bacterial endotoxin leakage from the small intestine due to increased intestinal permeability under alcohol challenge. The purpose of this study was to examine whether zinc pretreatment would inhibit acute ethanol-induced liver injury through prevention of intestinal permeability changes. Male 129 Sv(PC)J mice were treated with three intragastric doses of ZnSO4 at 5 mg of zinc ion per kg each dosing prior to acute ethanol challenge with a single oral dose of 6 g/kg ethanol. The zinc treatment did not alter the elevation of serum concentrations of alcohol. The acute ethanol exposure caused an elevation in serum alanine aminotransferase levels as well as fatty liver and hepatic degenerative necrotic foci as determined by biochemical assay and histochemical analysis, respectively. A significant increase in liver tumor necrosis factor-alpha (TNF-alpha) levels was detected by enzyme-linked immunosorbent assay. These pathological effects correlated well with increases in serum endotoxin levels. Importantly, acute ethanol treatment caused significant damage to the small intestine as determined by morphological analysis of intestinal sections and permeability assay. These alcohol-induced hepatic pathological changes and TNF-alpha elevation were significantly inhibited in the zinc-pretreated animals. The inhibitory action of zinc on alcohol-induced liver damage and activation of inflammation was associated with zinc suppression of alcohol-induced intestinal permeability changes. These results thus demonstrate that zinc prevention of increased intestinal permeability is importantly involved in the inhibition of acute ethanol-induced liver damage in mice.