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.

白细胞（LTS）是源自氧化的脂质物质 5-氟加氧酶之后的花生四烯酸的代谢 路径。 磺胺肽白细胞，LTC4，LTD4和LTE4， 10年前的结构表征为活动 过敏反应的缓慢反应物质的原理。 所以， 主要的兴趣集中在这些分子发挥的作用上 作为急性超敏反应的脂质介体以及 介导各种肺部疾病的支气管收缩物质 包括哮喘。 白三烯B4有多种动作相关 炎症，包括其有效的生物学活性作为 多形核白细胞的趋化因子。 主要的 关于角色的问题仍有待回答 白细胞在健康和疾病中发挥作用。 在很大程度上，这种缺乏 确定的信息是由于难以评估 合成部位的总生产。 白细胞是 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 有机体为无活性代谢产物。 其次，有很多 LT调节涉及的生化复杂性 生物合成以及细胞之间相互作用的复杂性 这会产生并响应这些调解人。 长期 拟议工作的目的是直接解决这两个 区域。 LTE4和LTB4代谢物的结构 将使用质量推导各种新陈代谢模型 光谱和辅助光谱技术。 目标是 确定白细胞的主要泌尿代谢物 动物和人并发展定量质谱法 测量这些化合物在液体中的外观的测定 作为尿液。 正常人中的代谢物的出现和 正常动物将被确定及其出现 患有慢性肺部疾病的患者和动物受到挑战 激活5-脂氧合酶途径。 第二个主要目标 拟议的研究计划是为了证明以下假设 白三烯A4充当跨细胞介体本身， 考虑生理相关的浓度 体内磺胺肽白细胞。 最近，潜在角色 发现血小板作为LTC4生产的位置。 经过 这种嗜中性粒细胞 - 血压相互作用的机制，初始 信号刺激含有LTA合酶但 没有LTC合酶可以将导致的信号转导 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。 关于该过程知之甚少 LTA4被带入血小板，此外，人们感到 抑制此过程可能是一种新颖的治疗策略 药物开发。