CHEMICAL-INDUCED HEPATOTOXICITY--CELL CELL INTERACTION

化学引起的肝毒性--细胞间相互作用

• 批准号: 2146518
• 负责人: JOELLYN M MCMILLAN
• 金额: $ 8.88万
• 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/2146518
• 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.

半乳糖胺是一种众所周知的肝毒素， 肝坏死 肝脏病变的外观长期以来一直是 与细胞UTP储存的消耗有关;然而， 谷胱甘肽和巯基化合物的晚期拯救也是 观察 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分泌活性 氧和谷胱甘肽是众所周知的细胞还原剂， 氧化应激可能通过以下方式导致半乳糖胺毒性 增加受损细胞对活性氧的暴露 物种 另一种假设是巨噬细胞分泌体液 这些因子通过特定的细胞受体起作用， 细胞抵抗毒性损伤的能力。 我们开发了一种 大鼠肝细胞培养系统，显示在体内的主要特征 半乳糖胺肝毒性，UTP耗竭，可通过 尿苷和谷胱甘肽再合成的抑制。 重要的是， 初步研究表明半乳糖胺对肝细胞的毒性 当细胞与活化的巨噬细胞共培养时增强。 我们相信我们有一个离体实验系统， 我们确定巨噬细胞是否会加剧半乳糖胺毒性 通过释放活性氧物质或通过释放 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 目前的研究是a）表征以下因素的加重作用： 活化的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细胞凋亡中的作用。 半乳糖胺（或其代谢物）的恶化，和d）检查 谷胱甘肽水平的调节对半乳糖胺毒性的影响 肝细胞培养物。