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CHEMICAL-INDUCED HEPATOTOXICITY--CELL CELL INTERACTION

化学引起的肝毒性--细胞间相互作用

基本信息

批准号：
2749501
负责人：
JOELLYN M MCMILLAN
金额：
$ 10.53万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 2000-07-31
项目状态：
已结题

项目摘要

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.

半乳糖胺是一种众所周知的肝毒素，可引起弥漫性局灶性肝损伤。肝坏死。肝脏病变的出现早已与细胞 UTP 储备的耗尽有关；然而耗尽谷胱甘肽和巯基化合物的后期救援也观察到。此外，库普弗细胞的激活可以增强半乳糖胺肝毒性。由于活化的巨噬细胞会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方式导致半乳糖胺毒性增加受损细胞与活性氧的接触物种。另一种假设是巨噬细胞分泌体液通过特定细胞受体起作用的因素，以减少细胞抵抗毒性损伤的能力。我们开发了一个初级显示体内主要特征的大鼠肝细胞培养系统半乳糖马因肝毒性，可逆的 UTP 耗竭尿苷，并抑制谷胱甘肽再合成。重要的是，初步研究表明，半乳糖胺对肝细胞有毒性当细胞与活化的巨噬细胞共培养时，这种能力得到增强。我们相信我们有一个离体实验系统，可以让我们确定巨噬细胞是否会加剧半乳糖胺毒性通过释放活性氧或通过释放体液因素。这项研究的长期目标是阐明半乳糖胺诱导肝坏死的机制的目标目前的研究目的是a）描述加剧影响的特征激活巨噬细胞对肝细胞培养物中半乳糖胺毒性的影响， b) 检查活性氧和体液因子在半乳糖胺（或其代谢物）的恶化，以及 d) 检查谷胱甘肽水平调节对半乳糖胺毒性的影响肝细胞培养物。