CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

这一合作努力的主要目标仍然是 对可能的化学介体进行化学和功能表征 支气管哮喘。主要的焦点将是定义 全动物模型细胞系统中的硫多肽白三烯 实验，并在正常的人类志愿者中，确定可能的 这些介质在人支气管哮喘病理生物学中的作用 它们在哮喘患者中作用的直接研究和放射免疫分析 (RIAS)在实验过程中它们在外周血中的出现 诱发和自发的哮喘发作。具体的 对人体细胞的生化和细胞学研究包括：分离 白三烯生物合成途径中的酶的定义 各种硫多肽白三烯的氧化失活产物 (LTC4、LTD4和LTE4)由人中性粒细胞、嗜酸性粒细胞、单核细胞和 肺泡巨噬细胞；肺泡巨噬细胞 硫多肽白三烯的生物转化对起效和持续时间的影响 人类呼吸道的伴随的体外痉挛反应；以及 最后，对肥大细胞异质性的定义出现在 人肺组织颗粒蛋白多糖和蛋白多糖的特性 IgE-Fc受体启动的产物的配置文件 花生四烯酸(LTC4、LTB4和PGD2)的氧化代谢。这个 活体动物模型的同伴研究将集中在贡献上 第二代环氧合酶产物和 对硫多肽作用的胆碱能反应的募集 雾化吸入和静脉注射对呼吸道组织中白三烯的影响 组胺、前列腺素D2和血管紧张素转换酶2的联合作用 硫多肽白三烯气雾剂外源性给药 不同的组合和顺序；以及对饮食的影响 对已知的对刺激的生理反应的操纵 导致白三烯的形成。在正常人和/或 指导哮喘患者确定发病地点、性质和时间进程。 吸入硫多肽白三烯对呼吸道反应的评价 不同化学介质组合对呼吸道反应的影响 特别注意可能认识到的非特定 高反应性；白三烯作用机理的测定 通过对受试者进行预处理的治疗干预的启示 色甘油钠、阿托品或类固醇；用放射免疫法测定 血浆中的硫多肽、白三烯及其代谢物LTB4和PGD2。

The major objective of this collaborative effort continues to be to characterize chemically and functionally the putative chemical mediators of bronchial asthma. The major focus will be to define the biology of the sulfidopeptide leukotrienes in model cellular systems, in whole animal experiments, and in normal human volunteers, and to determine the possible role of these mediators in the pathobiology of human bronchial asthma by direct studies of their actions in asthmatics and by radioimmunoassays (RIAs) for their appearance in peripheral blood during experimentally induced and spontaneous episodes of bronchial asthma. The specific biochemical and cellular studies with human cells include: the isolation of enzymes in the leukotriene biosynthetic pathway; the definition of the oxidative inactivation products of each of the sulfidopeptide leukotrienes (LTC4, LTD4 and LTE4) by human neutrophils, eosinophils, monocytes, and alveolar macrophages; the determination of the relationship of bioconversion of the sulfidopeptide leukotrienes to the onset and duration of the concomitant in vitro spasmogenic response of human airways; and finally, the definition of the heterogeneity of the mast cells present in human lung tissue by characterization of their granular proteoglycan and the IgE-Fc receptor-initiated profile of products generated from the oxidative metabolism of arachidonic acid (LTC4, LTB4, and PGD2). The companion studies in animal models in vivo will focus on the contributions of the secondary generation of cyclooxygenase products and of the recruitment of cholinergic responses to the action of the sulfidopeptide leukotrienes on airway tissue after both aerosol and intravenous administration; on the combined action of histamine, PGD2, and the sulfidopeptide leukotrienes when administered exogenously by aerosol in various combinations and sequences; and on the effects of dietary manipulation on the physiologic responses to stimuli that are known to result in leukotriene formation. The studies in normal humans and/or asthmatics are directed to determining the site, nature and time course of the airway responses to inhaled sulfidopeptide leukotriene; the assessment of the airway response to various combinations of chemical mediators with particular attention to the possible recognition of nonspecific hyperreactivity; the determination of mechanisms of leukotriene action with implications for therapeutic intervention by pretreating the subjects with sodium cromolyn, atropine, or steroids; and the measurement by RIA of the sulfidopeptide leukotrienes and their metabolites, LTB4 and PGD2, in plasma.