LEUKOTRIENES AND SLOW REACTING SUBSTANCE OF ANAPHYLAXIS

白三烯（LT）是从氧化代谢中获得的脂质物质。 5-脂氧合酶后花生四烯酸的代谢 通路 硫肽白三烯，LTC 4，LTD 4和LTE 4， 十年前的结构特征是 过敏反应的慢反应物质原理。 因此，我们认为， 人们的主要兴趣集中在这些分子所扮演的角色上 作为急性超敏反应的脂质介质，以及 支气管收缩物质介导各种肺部疾病 包括哮喘。 白三烯B4具有多种作用， 包括其作为一种有效的生物活性， 多形核白细胞的趋化因子。 主要 关于这一作用的问题仍有待回答， 白三烯在健康和疾病中起作用。 在很大程度上，这种缺乏 确切的信息是由于难以评估 在合成现场的总产量。 白三烯是 被认为是在微环境中起作用而不是循环; 此外，它们被迅速代谢并从体内消除。 生物体作为非活性代谢物。 其次，有很多 参与LT调节的生物化学复杂性 生物合成以及细胞间相互作用的复杂性 产生并回应这些中介的机制。 长期 拟议工作的目标是直接解决这两个问题， 地区 LTE 4和LTB 4的代谢产物的结构在 各种代谢模型将推导出使用质量 光谱和辅助光谱技术。 目标是 以确定尿中白三烯的主要代谢物， 动物和人类，并开发定量质谱 测定这些化合物在流体中的外观的分析 就像尿一样 正常人体内代谢产物的出现， 将确定正常动物以及它们的外观， 慢性肺病患者和动物， 激活5-脂氧合酶途径。 第二个主要目标 提出的研究计划，是测试的假设， 白三烯A4本身作为跨细胞介质， 考虑到生理相关浓度的 硫肽白三烯在体内。 最近，潜在的作用 发现血小板的一个部位的LTC 4生产。 通过 这种嗜血小板-血小板相互作用的机制， 信号刺激含有LTA合酶的中性粒细胞， 没有LTC合酶可以被转换成信号， LTC 4生物合成。 因此，认为跨细胞代谢 可能是解释急性与慢性 炎症反应。 我们对这一过程知之甚少， LTA 4被吸收到血小板中，而且，感觉到 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.