HUMAN MAST CELL AND BASOPHIL ARACHIDONIC ACID METABOLISM

人类肥大细胞和嗜碱性粒细胞是许多过敏性疾病的中心成分 疾病，如花粉热、某些形式的哮喘和过敏反应。什么时候 在过敏原或其他刺激的激活下，这些细胞释放各种不同的 促炎化学介质。其中最有力的是 分子是花生四烯酸(AA)的氧化产物，如 前列腺素(PG)和白三烯(LTS)，包括白三烯(C， D和E)，危害过敏反应的慢反应物质。我们有 最近开发的高度纯化人肺肥大细胞的方法和 嗜碱性细胞，并已开始表征AA代谢物的光谱 由这些细胞产生，生理和药物机制由 这些促炎物质的释放是可以控制的。 这项建议的中心目标是进一步描述AA代谢的特征 在人类肥大细胞和嗜碱性细胞中，希望这一信息将 导致了治疗这些疾病的新方法，通过操纵 AA代谢物的合成和释放。使用最近的 特性化的、高度特异的放射免疫分析，经High 进行高效液相色谱法，我们将确定肥大细胞和/或 嗜碱性细胞的触发导致白三烯B4的产生，一种有效的 中性粒细胞的趋化、趋化和激活因子 提示这种物质的释放延长了最初的炎症 肥大细胞/嗜碱性粒细胞触发的反应。我们将做好准备和 人关节滑膜组织中肥大细胞的特征 炎性关节成形术，并与人类肥大细胞比较 之前在我们的实验室中进行了表征。我们认为肥大细胞是 在炎症性关节疾病的发病机制中很重要，而人类 来自不同组织部位(滑膜组织和肺)的肥大细胞将 在激活它们的因素方面不同，AA的概况 它们释放的代谢物，以及它们的功能可以 从药理上调节的。我们将定义AA代谢物的光谱 由人类嗜碱性粒细胞在用~3H-AA预先标记后产生；我们 假设它们将产生环氧合酶代谢物，此外 与我们之前展示的白三烯C4的结合，并暗示它会触发 这会导致组胺的释放，但不会释放白三烯(例如C5a) 导致磷脂周转的模式不同于触发 导致组胺和白三烯的释放(如抗原、抗IgE、 离子浮体A23187)。通过这些对AA代谢的新见解， 人类肥大细胞和嗜碱性粒细胞，我们觉得临床上有用的方法 以治疗过敏性疾病，如哮喘，会产生。

Human mast cells and basophils are central elements in numerous allergic disorders, such as hay fever, some forms of asthma, and anaphylaxis. When activated by allergens or other stimuli, these cells release a variety of proinflammatory chemical mediators. Among the most potent of these molecules are oxygenated products of arachidonic acid (AA), such as prostaglandins (PGs) and leukotrienes (LTs), including the leukotrienes (C, D and E) which compromise slow reacting substance of anaphylaxis. We have recently developed methods for highly purifying human lung mast cells and basophils, and have begun to characterize the spectrum of AA metabolites produced by these cells, and physiologic and pharmacologic mechanisms by which the release of these proinflammatory substances can be controlled. The central aim of this proposal is to further characterize AA metabolism in human mast cells and basophils in the hope that this information will lead to new approaches to the treatment of these disorders, by manipulating the synthesis and release of AA metabolites. Using a recently characterized, highly specific radioimmunoassay with confirmation by high performance liquid chromatography, we will determine if mast cell and/or basophil triggering leads to the production of leukotriene B4, a potent chemotactic chemokinetic, and activating factor for human neutrophils; we suggest that the release of this material prolongs the initial inflammatory response initiated by mast cell/basophil triggering. We will prepare and characterize mast cells from human synovial tissue from patients with inflammatory arthropthies, and compare them with human mast cells previously characterized in our laboratory. We suggest that mast cells are important in the pathogenesis of inflammatory joint disease, and that human mast cells from different tissues sites (synovial tissue vs lung) will differ in terms of factors which activate them, the profile of AA metabolites that they release, and ways in which their function can be modulated pharmacologically. We will define the spectrum of AA metabolites produced by human basophils after prelabelling them with 3H-AA; we hypothesize that they will produce cyclooxygenase metabolites, in addition to leukotriene C4 that we have shown previously, and suggest that triggers which cause the release of histamine but not leukotrienes (e.g. C5a) will cause a different pattern of phospholipid turnover than triggers which cause release of histamine and leukotrienes (e.g. antigen, anti-IgE, ionophore A23187). With these new insights into the metabolism of AA in human mast cells and basophils, we feel that clinically useful approaches to the treatment of allergic disorders, such as asthma, will result.