HUMAN MAST CELL AND BASOPHIL ARACHIDONIC ACID METABOLISM

人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。 当 这些细胞被过敏原或其他刺激物激活后，会释放出多种 促炎化学介质。 其中最具潜力的 分子是花生四烯酸（AA）的氧化产物，例如 洋地黄素（PG）和白三烯（LT），包括白三烯（C， D和E），其损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， 嗜碱性粒细胞，并已开始表征AA代谢物的光谱 这些细胞产生的，和生理和药理机制， 从而可以控制这些促炎物质的释放。 该提案的中心目的是进一步表征AA代谢 在人类肥大细胞和嗜碱性粒细胞中，希望这些信息将 引导新的方法来治疗这些疾病，通过操纵 AA代谢物的合成和释放。 最近使用A 特征性、高特异性放射免疫分析， 通过高效液相色谱法，我们将确定肥大细胞和/或 嗜碱性粒细胞触发导致产生白三烯B4，一种有效的 人中性粒细胞的趋化性、趋化动力学和活化因子;我们 表明这种物质的释放抑制了最初的炎症反应， 由肥大细胞/嗜碱性粒细胞触发引发的反应。 我们会做好准备， 表征来自患有以下疾病的患者的人滑膜组织的肥大细胞 炎性关节病，并与人肥大细胞进行比较 在我们的实验室里， 我们认为肥大细胞 在炎性关节疾病的发病机制中很重要， 来自不同组织部位（滑膜组织与肺）的肥大细胞将 在激活它们的因素方面有所不同，AA的概况 它们释放的代谢物，以及它们的功能可以被 调变频率 我们将定义AA代谢物的光谱 用3 H-AA预标记后，由人嗜碱性粒细胞产生;我们 假设它们将产生环氧合酶代谢物，此外 我们之前已经展示过的白三烯C4，并建议触发 引起组胺释放但不引起白三烯（例如C5 a）释放的药物将 会导致不同的磷脂周转模式， 导致组胺和白细胞三烯（例如抗原、抗IgE， 离子载体A23187）。 随着这些新的见解AA的代谢， 人肥大细胞和嗜碱性粒细胞，我们认为临床上有用方法 用于治疗过敏性疾病，例如哮喘。

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.