The sulfidopeptide leukotrienes (LT) C4, D4, and E4, and platelet activating factor (PAF) are potent inflammatory mediators. They are released from the lung following immunologic and nonimmunologic stimuli, and they may play an important role in the pathogenesis of asthma and other inflammatory lung diseases. Many animal and in vitro studies have provided insight into their mechanism of action, however, the relevance of these studies to man is unclear because species differences exist in the responses to these compounds. Recent studies performed in several laboratories, including ours, have established the potency of these mediators in human subjects, and have begun to define their mechanism of action. The purposes of this study are to gain a better understanding of the mechanism by which these mediators produce bronchoconstriction and airway hyperreactivity in man, and develop alternative, more effective treatment strategies For asthma. To accomplish ese goals we will: (1) Further characterize the airway responses to inhaled LTD4 and PAF. (2) Test the effectiveness of putative leukotriene and PAF antagonists and lipoxygenase inhibitors. (3) Define the local mediator and cellular responses to inhaled LTD4 and PAF in normal subjects and to antigen in antigen-induced asthma. The airway responses to LTD4 and PAF will be determined by using a standard inhalation challenge technique and sensitive measures of presumably large airway (specific airway conductance) and small airway (flow rate at 30% of vital capacity after a partial forced expiratory maneuver) function. The local responses to LTD4, PAF and antigen will be determined by performing bronchoalveolar lavage (BAL) before and after inhalation challenge with these mediators and antigen. We will measure total cell count and differential count; concentrations of prostaglandins, leukotrienes, histamine and other potential inflammatory mediators; and indices of alveolar-capillary permeability. Finally, we will administer specific antagonists/inhibitors before the inhalation challenge and BAL are performed, and compare their effects on bronchoconstriction and airway hyperreactivity to their effects on the inflammatory response in the lung.
