CHEMICAL MEDIATORS OF ACUTE PULMONARY DISORDERS

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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.