NEUTROPHIL CHEMOTACTIC FACTOR AND ALCOHOLIC HEPATITIS

肝脏是乙醇新陈代谢的主要器官， 白三烯、前列腺素和血栓烷。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 有一个特定的摄取系统来去除白三烯和其他二十烷类化合物 从发行量来看。对LTB4的兴趣源于其强大的生物学活性 中性粒细胞趋化因子活性及其在体内的作用 导致中性粒细胞在中性粒细胞聚集和激活 发炎。肝细胞将LTB4代谢成非活性化合物； 因此，肝脏在生物体的终止中起着核心作用。 LTB4的活性。已发现乙醇可以改变LTB4的代谢 此外，观察到的代谢物保留了显著的生物学意义 活动。我们已经提出，肝细胞不能 通过代谢使LTB4失活可能会产生趋化梯度 哪些中性粒细胞可以被吸引。我们已经提出，如果LTB4是 当乙醇被摄取时，在肝脏的某个远端合成 人类，肝细胞将不能灭活积累的LTB4， 招募中性粒细胞入侵肝细胞。这一假设一直是 被我们称为远程站点假说，可能在 酒精性肝炎。考虑到这一假设，因此它是 有兴趣了解LTB4代谢的详细生物化学 乙醇存在时的肝细胞。 即使在相对较低的剂量(10-50 mM)乙醇代谢 肝细胞本身可能涉及许多与二十烷类化合物相关的酶。 代谢，包括酒精脱氢酶，过氧化氢酶， 微粒体细胞色素P-45o，并改变重要的辅助因子，如 NADH/NAD比值。乙醇代谢的产物乙醛可以 对各种酶也有影响，特别是与 过氧化氢酶和过氧化氢，过氧化物酶的β-氧化产物。其他 花生四烯酸的代谢物(二十烷类化合物，如前列腺素和 血栓素)也是由肝脏代谢的，目前尚不清楚 关于乙醇对这些化合物的代谢命运的影响。 由于二十烷类化合物具有无数的生物学特性，因此 肝细胞内或其他代谢细胞内的乙醇 二十烷类化合物，可能通过改变细胞对这些物质的反应而表现出来 脂类调节剂。对脂类介质代谢的认识 细胞激活的比例被乙醇和乙醛改变 对乙醇的生物化学影响的洞察，目前还没有 完全理解。

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.