CHEMICAL-INDUCED HEPATOTOXICITY--CELL CELL INTERACTION

化学引起的肝毒性--细胞间相互作用

• 批准号: 2458814
• 负责人: JOELLYN M MCMILLAN
• 金额: $ 10.37万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458814
• 关键词: biosynthesis; cell cell interaction; cell death; cytotoxicity; free radical oxygen; galactosamine; glutathione; hepatotoxin; humoral immunity; interleukin 1; laboratory rat; leukotrienes; liver cells; liver toxic disorder; macrophage; necrosis; nucleotide metabolism; oxidative stress; thromboxanes; tissue /cell culture; uridine triphosphate

Galactosamine is a well-known hepatotoxin that causes a diffuse focal hepatic necrosis. The appearance of the hepatic lesion has long been linked to depletion of cellular UTP stores; however depletion of glutathione and a late-phase rescue by sulfhydryl compounds are also observed. Furthermore, activation of Kupffer cells can enhance galactosamine hepatotoxicity. Since activated macrophages secrete active oxygen and glutathione is well-known cellular reductant, it is possible that oxidative stress may be contribute to galactosamine toxicity by increasing the exposure of the compromised cells to active oxygen species. An alternate hypothesis is that macrophages secrete humoral factors that act through specific cellular receptors to decrease the ability of the cell to resist toxic injury. We have developed a primary rat hepatocyte culture system that shows the major features of in vivo galactosmaine hepatotoxicity, UTP depletion that is reversible by uridine, and suppression of glutathione resynthesis. Of importance, preliminary studies have shown that galactosamine toxicity to hepatocytes is enhanced when the cells are cocultured with activated macrophages. We believe that we have an ex vivo experimental system that will allow us to determine whether macrophages exacerbate galactosamine toxicity through the release of active oxygen species or through the release of humoral factors. The long-term goal of this research is to elucidate the mechanism of galactosamine-induced hepatic necrosis. The objectives of the present studies are to a) characterize the exacerbating effect of activated macrophages on galactosamine toxicity in hepatocyte cultures, b) examine the roles of active oxygen species and humoral factors in the exacerbation of galactosamine (or its metabolites), and d) to examine the effect of modulation of glutathione levels on galactosamine toxicity in the hepatocyte cultures.

氨基半乳糖是一种广为人知的肝毒素，可引起弥漫性病灶。 肝脏坏死。长期以来，肝脏病变的出现一直是 与蜂窝UTP存储的耗尽有关；然而， 谷胱甘肽和一种通过巯基化合物进行的后期救援也是 观察到的。此外，Kupffer细胞的激活可以增强 氨基半乳糖肝毒性。由于激活的巨噬细胞分泌活性 氧和谷胱甘肽是众所周知的细胞还原剂，有可能 氧化应激可能通过以下途径导致氨基半乳糖中毒 增加受损细胞对活性氧的暴露 物种。另一种假说是巨噬细胞分泌体液 通过特定细胞受体作用的因子，以减少 细胞抵抗毒性损伤的能力。我们已经开发出一种主要的 显示体内主要特征的大鼠肝细胞培养体系 半乳糖胺肝毒性，UTP耗竭，可通过 尿苷和抑制谷胱甘肽的重新合成。重要的是， 初步研究表明，氨基半乳糖对肝细胞有毒性作用 当细胞与激活的巨噬细胞共同培养时，这种作用会增强。 我们相信，我们有一个体外实验系统，可以 美国将确定巨噬细胞是否加剧了氨基半乳糖毒性 通过释放活性氧物种或通过释放 体液因素。这项研究的长期目标是阐明 氨基半乳糖致肝坏死的机制。的目标 目前的研究是为了a)表征 激活的巨噬细胞对肝细胞培养中氨基半乳糖毒性的影响 B)研究活性氧物种和体液因素在 半乳糖胺(或其代谢物)的加重，以及d)检查 谷胱甘肽水平的调节对半乳糖胺毒性的影响 肝细胞培养。