LEUKOTRIENES AND SLOW REACTING SUBSTANCE OF ANAPHYLAXIS

白三烯(LTS)是由氧化反应产生的脂类物质。 花生四烯酸在5-脂氧合酶作用下的代谢 路径。硫多肽白三烯、LTC4、LTD4和LTE4， 10年前在结构上被描述为活跃的 过敏反应慢反应物质的原理。因此， 人们的主要兴趣集中在这些分子所起的作用上。 作为急性超敏反应的脂质介质以及 介导多种肺部疾病的支气管收缩物质 包括哮喘。白三烯B4具有多种作用相关 包括其强大的生物活性作为一种 中性粒细胞趋化因子。主修 关于这一角色的问题仍有待回答 白三烯在健康和疾病中发挥作用。在很大程度上，这种缺乏 确定的信息是由于评估的困难 合成现场的总产量。白三烯是 认为作用于微环境而不是循环的； 此外，它们被迅速新陈代谢，并从 作为非活性代谢物的有机体。其次，有大量的 与LT调节有关的生化复杂性 生物合成以及细胞间相互作用的复杂性 产生并回应这些调解人的人。长期的 拟议工作的目标是直接解决这两个问题 区域。LTE4和LTB4代谢产物的结构 不同的新陈代谢模型将用质量来推导 光谱和辅助光谱技术。我们的目标是 目的：鉴定白三烯的主要尿代谢物 动物和人类一样，并发展了定量质谱学 测量这些化合物在流体中的外观的分析方法 作为尿液。代谢物在正常人和正常人体内的出现 正常的动物将被确定以及它们在 慢性肺病患者和动物面临挑战 激活5-脂氧合酶途径。的第二个主要目标 提出的研究计划，是为了检验这样一个假设 白三烯A4本身就是一种跨细胞介体， 考虑到生理上相关的浓度 体内的硫多肽白三烯。最近，潜在的作用 发现了作为LTC4产生部位的血小板。通过 中性粒细胞-血小板相互作用的这种机制，最初是 刺激含有LTA合成酶的中性粒细胞的信号 任何LTC合酶都不能被转化为导致 LTC4的生物合成。因此，人们认为跨细胞代谢 可能是解释急性和慢性疾病的一个重要机制 炎症反应。人们对这一过程知之甚少。 LTA4被带入血小板，而且，人们认为 抑制这一过程可能是一种新的治疗策略 药物开发。

Leukotrienes (LTs) are lipid substances derived from the oxidative metabolism of arachidonic acid following the 5-lipoxygenase pathway. The sulfidopeptide leukotrienes, LTC4, LTD4, and LTE4, were structurally characterized 10 years ago as the active principles of slow reacting substance of anaphylaxis. Therefore, a major interest has centered around the role these molecules play as lipid mediators of acute hypersensitivity reactions as well as bronchoconstricting substances mediating various lung disorders including asthma. Leukotriene B4 has a multiple actions relevant to inflammation including its potent biological activity as a chemotactic factor for the polymorphonuclear leukocyte. Major questions remain to be answered concerning the role that leukotrienes play in health and disease. In large part, this lack of definitive information is due to the difficulties in assessing total production at the site of synthesis. Leukotrienes are thought to act in the microenvironment rather than circulating; furthermore, they are rapidly metabolized and eliminated from the organism as inactive metabolites. Secondly, there is a great deal of biochemical complexity involved in the regulation of LT biosynthesis as well as complexity in the interaction between cells that produce as well as respond to these mediators. A long term objective of the proposed work is to directly address these two areas. The structure of the metabolites of LTE4 and LTB4 in various models of metabolism will be deduced using mass spectrometric and ancillary spectroscopic techniques. The goal is to identify those major urinary metabolites of leukotrienes in animals as well as man and develop quantitative mass spectrometric assays to measure the appearance of these compounds in fluids such as urine. The appearance of metabolites in normal human beings and normal animals will be determined as well as their appearance in patients with chronic lung disease and animals challenged to activate the 5-lipoxygenase pathway. A second major goal of the proposed research program, is to testy the hypothesis that leukotriene A4 serves as a transcellular mediator itself, accounting for physiologically relevant concentrations of sulfidopeptide leukotrienes in vivo. Recently, the potential role of the platelet as a site of LTC4 production was discovered. By this mechanism of neutrophil-platelet interaction, an initial signal stimulating the neutrophil which contains LTA synthase but no LTC synthase could be transduced into a signal which leads to LTC4 biosynthesis. Thus, it is felt that transcellular metabolism might be an important mechanism explaining the acute versus chronic inflammatory response. Little is known about the process by which LTA4 is taken up into the platelet and furthermore, it is felt that inhibition of this process may be a novel therapeutic strategy for drug development.