The objective of this project is to develop a better understanding of the role of chemical mediators of anaphylaxis, particularly the sulfidopeptide leukotrienes LTC4, LTD4 and LTE4, in bronchial asthma. This goal will be approached through in vitro studies of excised human bronchial tissue and subpleural lung strips supplemented by analogous experiments with guinea pig pulmonary tissue. Sensitized pulmonary tissue preparations will be studied in organ baths. Airway smooth muscle contraction in response to specific antigen will be measured and, the bath fluid will be processed for the analysis of released mediators. The sulfidopeptide leukotrienes will be quantified by bioassay, radioimmunoassay and high performance liquid chromatography, and histamine will be measured by automated fluorometry. We will examine the effects of inhibitors of arachidonic acid metabolism and the inhibition of gamma-glutamyl transpeptidase on bronchospasm and sulfidopeptide leukotriene release. In other experiments we will compare the responsiveness of human bronchial tissue and peripheral lung strips to pharacological agents, including LTC4, LTD4 and LTE4, and to antigen. We will also study the effects of mediators of anaphylaxis and exposure to antigen on the response of human airway smooth muscle to contractile agonists and mechanical deformation. These studies will further define the role of sulfidopeptide leukotrienes in anaphylactic bronchospasm and in the modulation of human bronchial responsiveness, providing important insights regarding cellular processes involved in the pathogenesis of bronchial asthma.
