NEUTROPHIL CHEMOTACTIC FACTOR AND ALCOHOLIC HEPATITIS

中性粒细胞趋化因子与酒精性肝炎

• 批准号: 2389891
• 负责人: ROBERT Carl MURPHY
• 金额: $ 12.52万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/2389891
• 关键词: acetaldehyde; alcoholic hepatitis; chemical structure function; chemoattractants; coenzyme A; cytochrome oxidase; dosage; eicosanoid metabolism; enzyme inhibitors; ethanol; gas chromatography mass spectrometry; high performance liquid chromatography; laboratory rat; leukotrienes; liver metabolism; liver pharmacology; mass spectrometry; neutrophil; organelles; oxidation; prostaglandin F

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.

肝脏是乙醇代谢的主要器官， 白细胞三烯类、白细胞生成素类和血栓素类。白三烯B4是一种 已知由炎症细胞产生的花生四烯酸的代谢物 如多形核白细胞（中性粒细胞）和肝细胞 具有特定的吸收系统，以去除白三烯和其他类二十烷酸 从循环。对LTB 4的兴趣源于其强大的生物学活性， 作为中性粒细胞趋化因子的活性及其体内作用 导致中性粒细胞在出血部位的积聚和活化， 炎症肝细胞将LTB 4代谢成无活性化合物; 因此，肝脏在终止生物学上起着核心作用。 LTB 4的活性。已经发现乙醇改变LTB 4的代谢 此外，观察到的代谢物保留了显著的生物活性， 活动我们认为，肝细胞的失败， 通过代谢的ILTB 4可以产生趋化梯度， 哪些中性粒细胞可以被吸引。我们建议，如果LTB 4是 当乙醇被摄入时， 在人类中，肝细胞将不能抑制积聚的LTB 4， 募集中性粒细胞侵入肝细胞这一假设一直被 我们称之为远程站点假说，可能在以下方面发挥作用： 酒精性肝炎 考虑到这一假设， 有兴趣了解LTB 4代谢的详细生物化学， 当乙醇存在时肝细胞。 即使在相对低的剂量（10-50 mM）下， 肝细胞本身可涉及许多与类花生酸相关酶 代谢，包括醇脱氢酶，过氧化物酶体过氧化氢酶， 微粒体细胞色素P-45 O，并改变重要的辅助因子，如 NADH/NAD+比率。乙醇代谢的产物乙醛可以 也对各种酶有影响，特别是与 过氧化氢酶和H2 O2，过氧化物酶体β-氧化的产物。其他 花生四烯酸的代谢物（类二十烷酸，如洋地黄素， 血栓烷）也由肝脏代谢， 关于乙醇对这些化合物代谢命运的影响。 由于类二十烷酸具有无数的生物学特性， 乙醇在肝细胞内，或在其他细胞代谢， 类花生酸，可能表现为改变细胞反应，这些 脂质介质。 了解脂质介质的代谢 的细胞活化被乙醇和乙醛改变， 深入了解乙醇的生化作用，目前还没有 完全理解