The goal of this proposal is the better understanding of upper airways disease processes. Our approach will focus on the involvement of mast cells and basophils, the mediators they release, the plasma enzyme systems (kallikrein-kinin, Hageman Factor and complement), and the subsequent recruitment of other cell types. This will be accomplished with a recently developed in vivo model of allergic rhinitis which involves the recovery of inflammatory mediators after intranasal challenge with antigens to which the subject is sensitive. We have thus far found increased levels of several mast cell products (histamine, PGD2 and a TAMe esterase activity) associated significantly with the physiologic response to the allergen, sneezing. Initial studies will focus on: (1) The quantitaton and characterization of these and other mediators such as kinin, SRS and platelet-activating factor (AGEPC); (2) the use of pharmacologic agonists to characterize both the mechanism of release and the contribution of each mediator; (3) the extension of our preliminary observation which implicates mediator release in the late phase (6 - 12 hours) response to antigen; and (4) confirmation that the response to challenge of the nose with cold, dry air leads to mediator release. Future plans include morphologic examination of the early and late response to antigen to ascertain which cell types are involved and to describe the pathologic processes. We will also examine the response to other potential initiators of upper airways disease. Finally, this versatile model provides a means for comparing in vitro observations with mast cells and basophils with the in vivo response, and this will be vigorously pursued with our present collaborators.
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