Apoptosis and dysregulated ceramide metabolism in a murine model of alcohol-enhanced lipopolysaccharide hepatotoxicity
Apoptosis and dysregulated ceramide metabolism in a murine model of alcohol-enhanced lipopolysaccharide hepatotoxicity
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DOI：
10.1111/j.1530-0277.2000.tb04575.x
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发表时间：
2000-10-01
影响因子：
3.2
通讯作者：
McClain, CJ
中科院分区：
文献类型：
--
作者：
Deaciuc, IV;Nikolova-Karakashian, M;McClain, CJ
背景：细胞凋亡在乙醇诱导的肝损伤中的作用还没有得到太多的研究。因此，细胞凋亡是否是酒精性肝病的一个促成因素的问题仍有待回答。本研究的目的是描述酒精增强的脂多糖（LPS）hepatotoxic.Methods：小鼠模型中的肝细胞凋亡反应的特点：小鼠喂含酒精的液体饮食49天，然后由急性LPS的挑战。根据组织学外观、血浆肝酶活性（丙氨酸：2-酮戊二酸和天冬氨酸：2-酮戊二酸转氨酶，作为肝细胞溶解的标志物）和血浆透明质酸水平（作为窦内皮细胞清除功能的标志物）判断肝脏状态。通过DNA片段化（TUNEL程序）和半胱天冬酶-3和半胱天冬酶-8活性评估肝细胞凋亡反应。要确定是否神经酰胺发挥了作用，在肝脏的凋亡反应，酸性鞘磷脂酶和神经酰胺的组织含量的活性也quantited.Results：酒精暴露诱导脂肪积累和致敏的肝脏LPS损伤的影响。酒精可使血浆肝酶活性升高，LPS可增强此作用。肝细胞凋亡增加酒精和LPS治疗反映了高频率的阳性TUNEL染色细胞核和caspase-3和-8的活性增加。酸性鞘磷脂酶活性也增加，它与神经酰胺的组织含量升高。此外，LPS还增加血浆TNF-α水平。这些变化是伴随着血浆透明质酸升高，反映了受损的窦内皮细胞清除function.Conclusions：这些结果提供了一个更完整的描述酒精和LPS的肝细胞凋亡反应，并可能构成进一步的机制研究的基础上可能发挥作用的细胞凋亡在酒精性肝损伤。
Background: The role of apoptosis in EtOH-induced liver injury has not been investigated much. Therefore, the question whether apoptosis is a contributory factor to alcoholic liver disease remains to be answered. The purpose of this study was to characterize the liver apoptotic response in a murine model of alcohol-enhanced lipopolysaccharide (LPS) hepatotoxicity.Methods: Mice were fed an alcohol-containing liquid diet for 49 days followed by an acute LPS challenge. The liver state was judged on the basis of histological appearance, plasma liver enzyme activity (alanine:2-oxoglutarate and aspartate:2-oxoglutarate aminotransferases, as markers of hepatocytolysis), and plasma hyaluronan levels (as a marker of the sinusoidal endothelial cell scavenging function). The liver apoptotic response was assessed by DNA fragmentation (TUNEL procedure), and caspases-3 and -8 activity. To determine if ceramide played a role in the liver apoptotic response, the activity of acidic sphingomyelinase and tissue content of ceramide were also quantified.Results: Alcohol exposure induced fat accumulation and sensitized the liver to LPS injurious effects. Plasma liver enzyme activity was elevated by alcohol and this effect was potentiated by LPS. Liver apoptosis was augmented by both alcohol and LPS treatment as reflected by high frequency of positive TUNEL staining nuclei and by an increased activity of caspase-3 and -8. Acidic sphingomyelinase activity was also increased and it was associated with an elevated tissue content of ceramide. In addition, LPS also increased plasma TNF-alpha levels. These changes were accompanied by elevated plasma hyaluronan, reflecting an impaired sinusoidal endothelial cell scavenging function.Conclusions: These results provide a more complete description of the liver apoptotic response to both alcohol and LPS and may constitute the basis for further mechanistic studies on a possible role apoptosis may play in alcoholic liver injury.