LEUKOTRIENES AND SLOW REACTING SUBSTANCE OF ANAPHYLAXIS

白三烯和过敏反应的慢反应物质

• 批准号: 2215879
• 负责人: ROBERT Carl MURPHY
• 金额: $ 24.35万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-15 至 1998-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2215879
• 关键词: Macaca; anaphylaxis; bioassay; bronchospasm; chemical structure; eicosanoid metabolism; gas chromatography; gas chromatography mass spectrometry; guinea pigs; high performance liquid chromatography; human tissue; laboratory rat; leukotrienes; lipoxygenase; liver metabolism; lung disorder; mass spectrometry; neutrophil; oxygen; peroxisome; platelets; radiotracer; scintillation counter; stable isotope; thin layer chromatography; ultraviolet spectrometry; urinalysis

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.

白三烯 (LT) 是源自氧化酶的脂质物质 5-脂氧合酶后花生四烯酸的代谢 途径。 硫肽白三烯、LTC4、LTD4 和 LTE4， 10 年前在结构上被表征为活性 过敏反应慢反应物质的原理。 所以， 主要兴趣集中在这些分子所发挥的作用 作为急性超敏反应的脂质介质以及 介导各种肺部疾病的支气管收缩物质 包括哮喘。 白三烯 B4 具有多种相关作用 炎症，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。 主要的 关于其作用的问题仍有待回答 白三烯在健康和疾病中发挥作用。 在很大程度上，这种缺乏 确切信息的缺乏是由于评估的困难 合成现场的总产量。 白三烯是 被认为是在微环境中发挥作用而不是在循环中； 此外，它们会迅速代谢并从体内消除 有机体作为无活性的代谢物。 其次，还有很多 LT 调节涉及的生化复杂性 生物合成以及细胞间相互作用的复杂性 产生并对这些中介做出反应。 长期的 拟议工作的目标是直接解决这两个问题 地区。 LTE4和LTB4代谢物的结构 将使用质量推导出各种新陈代谢模型 光谱测定和辅助光谱技术。 目标是 鉴定白三烯的主要尿代谢物 动物和人类并开发定量质谱法 测量这些化合物在液体中的出现的测定，例如 如尿液。 正常人体内代谢物的出现 正常动物及其外观将被确定 患有慢性肺病的患者和面临挑战的动物 激活5-脂氧合酶途径。 该计划的第二个主要目标 提出的研究计划，是为了检验以下假设： 白三烯 A4 本身充当跨细胞介质， 考虑到生理相关浓度 体内硫肽白三烯。 最近，潜在的角色 发现血小板作为 LTC4 产生位点。 经过 中性粒细胞-血小板相互作用的这种机制，最初是 信号刺激含有 LTA 合酶的中性粒细胞，但 没有 LTC 合酶可以转导成导致 LTC4生物合成。 因此，人们认为跨细胞代谢 可能是解释急性与慢性的重要机制 炎症反应。 人们对这个过程知之甚少 LTA4 被吸收到血小板中，此外，感觉 抑制这一过程可能是一种新的治疗策略 药物开发。