ACTIVATED KUPFFER CELLS AND HEPATOTOXICITY

活化的干枯细胞和肝毒性

• 批准号: 2154565
• 负责人: PATRICIA E GANEY
• 金额: $ 10.21万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154565
• 关键词: Kupffer's cell; alcohols; allyl compound; arginine; electron microscopy; endopeptidases; glutathione; hepatotoxin; laboratory rat; liver function; liver metabolism; liver toxic disorder; statistics /biometry; tissue /cell culture; toxicant interaction; tumor necrosis factor alpha; tumor necrosis factor beta

When activated, Kupffer cells (KCs), the fixed tissue macrophages of the liver, release mediators such as reactive oxygen species, cytokines and proteolytic enzymes that could contribute to hepatocellular damage. The possibility that stimulation of KCs plays a role in chemical-induced liver injury has not been explored as a general mechanism of toxicity. The proposed research will address the hypothesis that activated KCs contribute to hepatotoxicity caused by some toxicants and will explore mechanisms by which this may occur. Studies will focus on allyl alcohol (AA) because preliminary evidence suggests that AA activates KCs and that KCs play a role in AA-induced hepatotoxicity. Initial studies to investigate the hypothesis that KCs contribute to AA-induced hepatotoxicity will be conducted to evaluate the time course of activation of KCs and the development of hepatocellular injury in AA-treated rats in vivo to determine the temporal relation between KC activation and toxicity. In addition, KC activity will be enhanced or inhibited in AA-treated rats to determine whether modulation of KC activity alters AAinduced hepatotoxicity. Furthermore, the ability of KCs to potentiate AA-induced toxicity to isolated hepatic parenchymal cells will be examined. A parallel series of experiments will be conducted with an active metabolite of AA, acrolein, to establish the role of this metabolite in KC-dependent injury to parenchymal cells. Experiments will be performed to determine whether the mechanism by which KCs enhance AA-induced toxicity involves KC-derived mediators. The possible involvement of reactive oxygen species, lysosomal enzymes, tumor necrosis factor, and metabolites of L-arginine will be examined. Finally, studies are proposed to determine whether the periportal nature of toxicity due to AA can be explained by differences in KC function in periportal and pericentral regions of the liver lobule. An overall goal of this research is to study mechanisms by which activated KCs may contribute to hepatotoxicity. The proposed experiments focus on AA, but the ultimate intent is to extend these studies to other hepatotoxicants. The results should provide understanding of the mechanisms by which activated KCs contribute to liver toxicity.

激活时，库普弗细胞（KCS），固定组织巨噬细胞 肝脏，释放介质，例如活性氧，细胞因子 和蛋白水解酶，可能有助于肝细胞壁损伤。 KCS刺激在化学诱导的可能性 肝损伤尚未作为毒性的一般机制探索。 拟议的研究将解决激活KCS的假设 有助于某些有毒物质引起的肝毒性，并将探索 可能发生这种情况的机制。 研究将重点放在烯醇酒精上 （AA）由于初步证据表明AA激活KC，并且 KCS在AA引起的肝毒性中发挥了作用。 最初的研究以研究KCS的假设 将有助于AA引起的肝毒性，以评估 KCS激活的时间过程和肝细胞的发展 体内AA处理的大鼠损伤以确定时间关系 在KC激活和毒性之间。 此外，KC活动将是 在AA处理的大鼠中增强或抑制，以确定是否调制 KC活性的改变会改变肝毒性。 此外，能力 KCS的增强AA诱导的毒性对孤立的肝实质 将检查细胞。 一系列平行的实验将是 用AA，Acrolein的活性代谢物进行的，以建立 该代谢产物在KC依赖性损伤对实质细胞中的作用。 将进行实验以确定是否 KC增强AA诱导的毒性的机制涉及KC衍生 调解人。 活性氧的可能参与， L-精氨酸的溶酶体酶，肿瘤坏死因子和代谢产物 将被检查。 最后，提出了研究以确定是否 差异可以解释因AA引起的毒性的周围性质 在肝小叶的周围和周围区域的KC功能中。 这项研究的总体目标是研究机制 激活的KC可能有助于肝毒性。 提议 实验的重点是AA，但最终的意图是扩展这些 研究其他肝毒性。 结果应提供 了解激活的KC促进的机制 肝毒性。