CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

这一合作努力的主要目标仍然是 表征化学和功能的推定的化学介质 支气管哮喘 主要的重点将是定义生物学的 在整个动物模型细胞系统中硫肽白三烯 实验，并在正常的人类志愿者，并确定可能的 这些介质在人支气管哮喘病理生物学中的作用 通过放射免疫测定法直接研究它们在哮喘中的作用 （RIA）在实验期间外周血中出现 诱发和自发性支气管哮喘发作。 具体 用人类细胞进行的生物化学和细胞研究包括： 酶在白三烯生物合成途径的定义; 每种硫肽白三烯的氧化失活产物 (LTC4、LTD 4和LTE 4）被人嗜中性粒细胞、嗜酸性粒细胞、单核细胞和 肺泡巨噬细胞;测定 硫肽白三烯的生物转化的开始和持续时间 人体气道的伴随体外痉挛反应;以及 最后，对肥大细胞的异质性的定义， 人肺组织颗粒蛋白聚糖表征 由IgE-Fc受体启动的产物谱 花生四烯酸（LTC 4、LTB 4和PGD 2）的氧化代谢。 的 在体内动物模型的伴随研究将集中在贡献 环加氧酶产物的二代和 对硫肽作用的胆碱能反应的募集 在气雾剂和静脉内给药后， 给药;对组胺，PGD 2和 当通过气雾剂外源性给药时， 各种组合和顺序;以及饮食的影响 操纵对已知刺激的生理反应， 导致白三烯形成。 在正常人和/或 哮喘患者被引导来确定哮喘发作的部位、性质和时间过程。 吸入硫肽白三烯的气道反应;评估 气道对化学介质的各种组合的反应， 特别注意可能承认非特定 高反应性;测定白三烯作用机制， 对受试者进行预治疗的治疗干预的意义 克罗埃因钠、阿托品或类固醇;以及通过RIA测量 血浆中的硫肽白三烯及其代谢物LTB 4和PGD 2。

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.