THE INVOLVEMENT OF KUPFFER CELLS IN CARBON-TETRACHLORIDE TOXICITY
THE INVOLVEMENT OF KUPFFER CELLS IN CARBON-TETRACHLORIDE TOXICITY
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DOI：
10.1006/taap.1993.1069
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发表时间：
1993-04-01
影响因子：
3.8
通讯作者：
THURMAN, RG
中科院分区：
文献类型：
--
作者：
EDWARDS, MJ;KELLER, BJ;THURMAN, RG
四氯化碳（CCl 4）是一种典型的中心周围肝毒性物质;然而，其作用机制的确切细节仍然未知。一种可能性是库普弗细胞参与该机制，因为CCl 4升高钙，并且库普弗细胞释放毒性类花生酸和细胞因子是钙依赖性的。因此，这些研究旨在评估枯否细胞在大鼠体内CCl 4毒性中的作用。在给予CCl_4（4 g/kg IG）前1天，用氯化钆处理（10 mg/kg GdCl_3 iv）选择性地破坏枯否细胞。CCl 4处理后24小时，麻醉大鼠，抽取血样用于天冬氨酸转氨酶（AST）测定，这是实质细胞损伤的指示，并将台盼蓝注入肝脏以染色死肝细胞的细胞核。AST水平在正常范围内，并且在溶剂或GdCl 3处理大鼠的肝脏中台盼蓝染色可忽略不计。正如预期的那样，单独的CCl 4处理将AST水平升高至超过4000 U/L的值，并引起大量细胞死亡（60-90台盼蓝阳性细胞/中央周围视野）。与此相反，GdCl 3处理几乎完全阻止了CCl 4引起的AST升高和细胞死亡。为了理解这一现象，对代谢和解毒途径进行了评估。CCl 4经细胞色素P450 II. E代谢。1;然而，GdCl 3处理并没有改变这一途径进行评估，从对硝基邻苯二酚形成的选择性底物，对硝基苯酚。GdCl 3处理对肝脏谷胱甘肽水平也没有影响。另一方面，GdCl 3治疗显着减少了中性粒细胞的浸润，导致暴露于CCl 4。这些数据清楚地支持了枯否细胞参与CCl 4体内毒性机制的假设，可能是通过释放中性粒细胞的趋化因子。
Carbon tetrachloride (CCl4) is a classical pericentral hepatotoxicant; however, precise details of its mechanism of action remain unknown. One possibility is that Kupffer cells participate in this mechanism since CCI4 elevates calcium, and the release of toxic eicosanoids and cytokines by Kupffer cells is calcium-dependent. Therefore, these studies were designed to evaluate the role of Kupffer cells in CCl4toxicity in the rat in vivo. Kupffer cells were destroyed selectively with gadolinium chloride treatment (10 mg/kg GdCl3iv) 1 day prior to administration of CCl4(4 g/kg ig). Twenty-four hours after CCl4treatment, rats were anesthetized, blood samples were drawn for aspartate aminotransferase (AST) determination, which is indicative of parenchymal cell damage, and trypan blue was infused into the liver to stain the nuclei of dead hepatocytes. AST levels were in the normal range and trypan blue staining was negligible in livers from vehicle- or GdCl3-treated rats. As expected, CCl4treatment alone elevated AST levels to values over 4000 U/liter and caused massive cell death (60-90 trypan blue-positive cells/ pericentral field). In dramatic contrast, the elevation in AST and cell death due to CCl4were almost completely prevented by GdCl3treatment. In attempts to understand this phenomenon, metabolic and detoxification pathways were assessed. CCl4is metabolized via cytochrome P450 II.E. 1; however, GdCl3treatment did not alter this pathway as assessed from p-nitrocatechol formation from the selective substrate, p-nitrophenol. GdCl3treatment also had no effect on hepatic glutathione levels. On the other hand, GdCl3treatment significantly reduced infiltration of neutrophils resulting from exposure to CCl4. These data clearly support the hypothesis that Kupffer cells participate in the mechanism of toxicity of CCl4in vivo, possibly by release of chemoattractants for neutrophils.