The principal goal of the program is to define the immunological roles of diverse mediators in selected human hypersensitivity, inflammatory, and fibrosing diseases. Mediators of inflammation generated by the 15-lipoxygenation of arachidonic acid in human keratinocytes, neuropeptide-like principles derived from immunological cells, and fibroblast-activating polypeptide secreted by human mononuclear phagocytes will be purified for structural studies, analyses of the structural bases for activity of the synthetic mediators, and the development of sensitive radioassays. The molecular and cellular properties of human leukocyte receptors for leukotriene C4 and leukotrienes D4/E4, that selectively transduce increases in leukocyte adherence to surfaces, will be elucidated and utilized to prepare chemical and immunochemical probes of the expression of the same receptors in skin and lung tissues in various diseases. The leukotrienes, other arachidonic acid metabolites, neuropeptides, and phospholipid platelet-activating factors (PAFs) that contribute to the altered vascular-alveolar permeability of adult respiratory distress syndrome and to the inflammatory reaction of allergic rhinitis will be identified and the synthetic mediators studied for effects in human airways. Functional, chromatographic, and radioassays for the PAFs will be established in order to examine the involvement of this mediator in adverse human reactions to physical, chemical, and immunological exposures. The capacity of oxygenation products of arachidonic acid in the central nervous system to mediate the nociception of inflammation in several rat models will be investigated by characterizing the endogenous factors and the effects of administering the factors exogenously. The suppression of PMN leukocyte function achieved by ingestion of eicosapentaenoic acid will be used to assess the role of airway inflammation in the bronchial hyperreactivity induced by ozone and by exercise and inhaled antigen in predisposed subjects. Core laboratories are to be established to provide for all projects standardized methods to quantify mediators, determine the structures of enzymes and receptors, assess the functions of mediators, and characterize the properties of receptors for mediators. The mechanisms of endogenous regulation and the possibilities for pharmacological control of generation and expression of mediators will be evaluated in relation to a range of allergic, dermatological, neurological, and pulmonary diseases.
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