Late phase asthmatic responses (LAR) are essential to an understanding of chronic symptomatic asthma. Platelet Activating Factor (PAF), a unique phospholipid, can induce nonspecific bronchial hyper-responsiveness (NSBHR), and produce a LAR. The hypothesis of this proposal is that (1) PAF is singularly responsible for the LAR and chronic allergic asthma, and platelets are necessary for this response to take place, and (2) that platelets accumulate in the lungs during a LAR to release certain mediators which cause basophil histamine release, attract eosinophils, and induce NSBHR. These autocoids may directly affect bronchial smooth muscle, basophils, or mast cells, and act synergistically with PAF to cause airway smooth muscle bronchospasm or hyperplasia. Methods: We will use the allergic rabbit model for LAR in New Zealand white rabbits by immunizing neonatal rabbits on the day of birth to preferentially produce antigen specific IgE antibody. Following immunization, these animals have NSBHR which is further increased by antigen challenge. Early and LAR are quantitated using standard pulmonary physiologic techniques in anesthesized rabbits. Specifically, we plan to: 1) determine if PAF alone will initiate late phase asthma airway inflammation, and NSBHR, or if activated platelets are also necessary; 2) determine the relationship between PAF and LAR with the use of specific PAF antagonists and platelet depletion; 3) determine if autocoids are generated by activated platelets which induce inflammation or NSHBR: 4) determine if leukotrienes and PAF act synergistically to induce the LAR or NSBHR: and 5) determine if platelets pool in the lung during the LAR to participate in the release of mediators. Significance: LAR helps explain chronic allergic asthma. PAF can induce late responses, inflammation and NSBHR. Platelets and their products may be involved in this response with PAF to attract eosinophils and degranulate basophils. If this hypothesis is true, a new understanding of asthma may be forthcoming and improved antagonists of PAF of eosinophil migration and release may directly benefit the treatment of allergic asthma.
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