The role of platelet activating factor in allergic disease

Asthma is a chronic inflammatory disease. In genetically predisposed individuals airborne allergens can trigger symptoms. The sensitivity of the lungs to allergens can be paralleled by skin sensitivity, and the similarity in clinical, pathological and pharmacological profiles of these two reactions has led to the hypothesis that similar mechanisms may underlie cutaneous and airway allergic reactions. Numerous inflammatory mediators have been implicated in the pathogenesis of allergic disease including platelet activating factor (PAF) which mimics certain aspects of the allergic response in the skin and airways. The aims of this thesis were to evaluate available antagonists of PAF in man, and to use these drugs to evaluate the potential role of PAF in allergic reactions in the skin and lungs in double-blind cross-over studies. Intradermal PAF induced dose-related weal and flare reactions in normal subjects. Triazolam failed to inhibit these responses at clinically effective sedative doses. Intradermal allergen induced dose related acute and late responses. BN 52063, which had previously been shown to inhibit the skin responses to PAF, inhibited the late, but not the early response to antigen. Inhaled PAF induced bronchoconstriction and neutropenia but not bronchial hyperresponsiveness (BHR) in normal subjects. BN52063 partially inhibited the effects of inhaled PAF. Changes in PAF challenge methodology failed to induce clinically significant changes in BHR. A pilot study suggested that atopic status may be an important determinant of the response. In view of these results a guinea pig model which closely mimicked accepted clinical allergen challenge procedures was developed. Using this technique, inhaled PAF failed to induce BHR, but inhaled allergen induced significant BHR, which was inhibited by WEB 2086. PAF induced oedema has been implicated in the genesis of BHR, but neither PAF nor allergen induced significant oedema at times of maximal bronchoconstriction or BHR. These results suggests that PAF may play a role in allergen-induced cutaneous responses and airway hyperresponsiveness but not through inducing bronchial oedema