ENDOTOXIN ENHANCEMENT OF HEPATOTOXICITY--ROLE OF PGD2

内毒素增强肝毒性--PGD2的作用

基本信息

批准号：
6350814
负责人：
PATRICIA E GANEY
金额：
$ 18.85万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-02-01 至 2003-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6350814
关键词：
Kupffer's cell alcohols allyl compound biological signal transduction calcium flux carbohydrate metabolism cytotoxicity drug interactions endotoxins hepatotoxin laboratory rat lipopolysaccharides mixed tissue /cell culture monocrotaline prostaglandins protein biosynthesis

项目摘要

DESCRIPTION (Adapted from the Investigator's Abstract): Lipopolysaccharide (LPS or endotoxin) from gram-negative bacteria produces a multitude of adverse biological effects in humans and experimental animals. Exposure to LPS occurs normally in humans because of leakage of bacterial products from the gastrointestinal tract into the portal circulation; however, under some conditions, this translocation increases, subjecting the liver to exposure to greater concentrations of LPS. This exposure to LPS can influence toxic responses to xenobiotic agents. For example, the investigator's recent studies demonstrate that small doses of LPS markedly enhance the hepatotoxicity of allyl alcohol (AA) and of monocrotaline (MCT), and similar potentiation of toxicity by LPS has been documented for other hepatotoxicants. Thus, the amount of LPS to which the liver is exposed may be a determinant of the magnitude of response to chemical insult. The overall goal of this application is to explore mechanisms by which LPS influences chemical-induced hepatotoxicity, and initial studies will focus on AA as a model periportal hepatotoxicant. Some studies will also be performed with MCT, a centrilobular hepatotoxicant. Recent results indicate that Kupffer cells (KCs) play a critical role in enhancement of AA-induced injury by LPS. LPS activates KCs to release a number of soluble mediators, including prostaglandin D2 (PGD2), and preliminary results indicate that PGD2 increases the cytotoxicity of AA toward hepatic parenchymal cells (HCs) in vitro. The hypothesis to be tested is that PGD2, released by KCs stimulated with LPS, increases the susceptibility of HCs to subsequent insult by hepatotoxicants such as AA and MCT. A combination of in vivo and in vitro approaches will be used in these studies. Studies in Aim 1 will test whether exposure of liver to PGD2 increases the hepatotoxicity response to AA or MCT by addressing the following hypotheses: a) exposure of HCs to PGD2 increases AA and MCT cytotoxicity, b) LPS-activated KCs increases cytotoxicity in HCs by a mechanism dependent on PGD2, c) inhibition of PGD2 synthesis in vivo attenuates LPS-induced enhancement of hepatotoxicity, and d) administration of PGD2 into the hepatic circulation increases hepatotoxicity. Studies in Aim 2 will reveal mechanisms by which PGD2 increases sensitivity of HCs to toxicity of AA or MCT by testing whether any of the following contribute to LPS enhancement of hepatotoxicity: a) PGD2-induced alterations in energy production, b) PGD2-induced inhibition of protein synthesis, and/or c) a PGD2 induced increase in intracellular calcium concentration. Results of these experiments will increase the understanding of how KC-derived inflammatory mediators affect the liver during exposure to hepatotoxicants. Furthermore, they will begin to reveal the mechanisms by which small doses of LPS determine sensitivity to chemical insult.

描述（改编自调查员的摘要）：脂多糖革兰氏阴性细菌（LPS或内毒素）产生多种人类和实验动物的不良生物学作用。接触 LPS通常发生在人类中，因为细菌产物从进入门户循环的胃肠道；但是，在一些条件，这种易位增加，使肝脏暴露到更大的LP。这种暴露于LP会影响有毒对异生元素的反应。例如，调查员的最新研究表明，一小剂量的LP显着增强了烯丙基醇（AA）和单蛋白（MCT）的肝毒性和类似 LPS已记录了其他毒性的增强肝毒性。因此，暴露于肝脏的LP可能成为对化学侮辱的反应大小的决定因素。这该应用的总体目标是探索LPS的机制影响化学引起的肝毒性，初步研究将集中在AA上作为模型外周肝毒性。一些研究也将是用MCT（一种心孔肝毒性剂）进行。最新结果表明 Kupffer细胞（KCS）在增强AA诱导的 LPS受伤。 LPS激活KCS以释放许多可溶性介体，包括前列腺素D2（PGD2）和初步结果表明 PGD2增加了AA对肝实质细胞（HCS）的细胞毒性体外。要检验的假设是pGD2，KCS发布用LP刺激，增加了HCS对随后的敏感性受AA和MCT等肝毒性剂的侮辱。体内和这些研究将使用体外方法。 AIM 1的研究将测试肝脏暴露于PGD2是否会增加肝毒性反应通过解决以下假设来向AA或MCT进行：a）HCS暴露于 PGD2增加了AA和MCT细胞毒性，B）LPS激活的KCS增加 HCS中的细胞毒性通过依赖PGD2的机制，c）抑制PGD2 体内合成可减轻LPS诱导的肝毒性的增强，并减弱 d）将PGD2施加到肝循环中增加肝毒性。 AIM 2中的研究将揭示PGD2的机制通过测试是否有任何人，可以提高HC对AA或MCT毒性的敏感性以下有助于LPS增强肝毒性：A） PGD2诱导的能源产生改变，b）PGD2诱导的抑制蛋白质合成和/或c）PGD2诱导细胞内增加钙浓度。这些实验的结果将增加了解KC衍生的炎症介质如何影响肝脏在接触肝毒性剂期间。此外，他们将开始揭示小剂量LPS确定化学敏感性的机制侮辱。