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NEUTROPHIL CHEMOTACTIC FACTOR AND ALCOHOLIC HEPATITIS

中性粒细胞趋化因子与酒精性肝炎

基本信息

批准号：
2682972
负责人：
ROBERT Carl MURPHY
金额：
$ 13.37万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-04-01 至 1999-03-31
项目状态：
已结题

项目摘要

The liver is a major organ for the metabolism of ethanol as well as leukotrienes, prostaglandins, and thromboxanes. Leukotriene B4 is a metabolite of arachidonic acid known to be produced by inflammatory cells such as the polymorphonuclear leukocyte (neutrophil) and the hepatocyte has a specific uptake system to remove leukotrienes and other eicosanoids from the circulation. Interest in LTB4 stems from its potent biological activity as a chemotactic factor for the neutrophil and its role in vivo causing accumulation and activation of neutrophils at the site of inflammation. The hepatocyte metabolizes LTB4 into inactive compounds; thus the liver plays a central role in the termination of biological activity of LTB4. Ethanol has been found to alter the metabolism of LTB4 and furthermore the observed metabolites retain significant biological activity. We have suggested that the failure of the hepatocyte to inactivate LTB4 by metabolism may generate a chemotactic gradient with which neutrophils can be attracted. We have suggested that if LTB4 is synthesized at some distal site to the liver when ethanol is ingested by humans, hepatocytes will fail to inactivate the accumulating LTB4, recruiting neutrophils to invade the hepatocyte. This hypothesis has been termed by us as the remote-site hypothesis and may play a role in alcoholic hepatitis. With this hypothesis in mind it is therefore of interest to understand the detailed biochemistry of LTB4 metabolism in the hepatocyte when ethanol is present. Even at relatively low doses (10-50 mM) ethanol metabolism in the hepatocyte can itself involve numerous enzymes relevant to eicosanoid metabolism, including alcohol dehydrogenase, peroxisomal catalase, microsomal cytochrome P-45O, and alter important cofactors such as the NADH/NAD+ ratio. The product of ethanol metabolism, acetaldehyde, can also have effects on various enzymes, in particular an interaction with catalase and H2O2, a product of peroxisomal beta-oxidation. Other metabolites of arachidonic acid (eicosanoids such as prostaglandins and thromboxanes) are also metabolized by the liver and nothing is known about the effects of ethanol on the metabolic fate of these compounds. Since eicosanoids have a myriad of biological properties, an effect of ethanol within the hepatocyte, or in other cells that metabolize eicosanoids, may be manifested by altered cellular responses to these lipid mediators. An understanding of how metabolism of lipid mediators of cell activation are altered by ethanol and acetaldehyde may provide insight into the biochemical effects of ethanol which at present are not fully understood.

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