INACTIVATION OF KUPFFER CELLS PREVENTS EARLY ALCOHOL-INDUCED LIVER-INJURY
INACTIVATION OF KUPFFER CELLS PREVENTS EARLY ALCOHOL-INDUCED LIVER-INJURY
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DOI：
10.1002/hep.1840200227
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发表时间：
1994-08-01
期刊：
影响因子：
13.5
通讯作者：
THURMAN, RG
中科院分区：
文献类型：
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作者：
ADACHI, Y;BRADFORD, BU;THURMAN, RG
众所周知，饮酒导致肝脏疾病呈剂量依赖性；然而，确切的机制尚不清楚。可能涉及高代谢状态后的缺氧；因此，当最近观察到Kupffer细胞的失活阻止了酒精对肝脏氧摄取的刺激时，Kupffer细胞参与最终导致酒精诱导的肝脏疾病的早期事件的想法成为了一种真正的可能性。这项研究的目的是验证这一假设。采用Tsukamoto和French建立的模型，雄性Wistar大鼠连续灌胃接触乙醇4周。在这个模型中，乙醇引起脂肪肝、坏死和炎症，这是人类酒精性肝病的特征变化。Kupffer细胞每周两次用选择性Kupffer细胞毒物氯化钆（GdCl3）灭活。暴露于乙醇2周和4周后，AST水平分别升高至192 +/- 13和244 +/- 56 IU/L（控制值为88 +/- 7）。GdCl3治疗几乎完全避免了这种损伤。GdCl3治疗后，脂肪变化、炎症和坏死均明显减轻。乙醇处理4周大鼠肝脏病理评分平均为4.3 +/- 0.6，乙醇和gdcl3处理大鼠肝脏病理评分为1.8 +/- 0.5，差异有统计学意义（p < 0.05）。在暴露于乙醇2至4周的大鼠中，乙醇消除率提高了2至3倍。这种升高被GdCl3治疗阻断。这些结果表明，GdCl3可预防酒精诱导的肝损伤，并强烈提示Kupffer细胞参与疾病过程的早期阶段。因此，对库普弗细胞功能的药理学操作可能是临床治疗酒精性肝损伤的一种新方法。
It is well recognized that consumption of alcohol leads to liver disease in a dose-dependent manner; however, the exact mechanisms remain unclear. Hypoxia subsequent to a hypermetabolic state may be involved; therefore, when it was observed recently that inactivation of Kupffer cells prevented stimulation of hepatic oxygen uptake by alcohol, the idea that Kupffer cells participate in early events that ultimately lead to alcohol-induced liver disease became a real possibility. The purpose of this study was to test that hypothesis. Male Wistar rats were exposed to ethanol continuously by means of intragastric feeding for up to 4 weeks using the model developed by Tsukamoto and French. In this model, ethanol causes fatty liver, necrosis and inflammation-changes characteristic of alcohol-induced liver disease in human beings. Kupffer cells were inactivated by twice weekly treatment with gadolinium chloride (GdCl3), a selective Kupffer cell toxicant. AST levels were elevated to 192 +/- 13 and 244 +/- 56 IU/L in rats exposed to ethanol for 2 and 4 wk, respectively (control value, 88 +/- 7). This injury was prevented almost completely by GdCl3 treatment. Fatty changes, inflammation and necrosis were also all reduced dramatically by GdCl3 treatment. The average hepatic pathological score of rats treated with ethanol for 4 wk was 4.3 +/- 0.6, which was reduced significantly in ethanol- and GdCl3-treated rats to 1.8 +/- 0.5 (p < 0.05). Rates of ethanol elimination were elevated 2- to 3-fold in rats exposed to ethanol for 2 to 4 wk. This elevation was blocked by GdCl3 treatment. These results demonstrate that GdCl3 prevents alcohol-induced liver injury and suggest strongly that Kupffer cells participate in the early phases of the disease process. Thus, pharmacological manipulation of Kupffer cell function might represent a new approach to clinical management of alcohol-induced liver injury.