The late pulmonary response (LPR) after antigen challenge in patients with asthma is poorly responsive to bronchodilators and often requires corticosteroids for resolution. The pathogenesis of these reactions is unclear with both IgE and non-IgE mediated mechanisms proposed to explain these reactions. The recent description of a model of LPPs in rabbits immunized from birth to produce antigen-specific IgE with or without antigen-specific IgG had demonstrated that IgE-allergen interactions can produce an LPR, and the IgG blunts rather than enhances this response (Am Pev Respir Dis 126:493, 1982). The LPR was also produced by passive transfer of the IgE, thus showing the response can occur in the absence of cellular immune mechanisms. This proposal will use this model to address 4 major questions: 1) What pathologic alterations occur within the lungs and airways during the development of an LPR? The pathology is anticipated to display cellular infiltrates (neutrophils and eosinophils) and edema without significant deposition of immune complexes and complement. 2) What are the detailed physiologic alterations that occur during the LPR? A central hypothesis is that allergen inhalation causes early alterations in small airway function that are not manifest in standard measurements of airway resistance until the dysfunction increases to involve large airways. In addition, increases in small airway resistance will correlate with the degree of small airway inflammation. 3) What mediators are responsible for the LPR in this animal model? The main hypothesis is that the LPR is an immunologically initiated (IgE) inflammatory response that involves mediators from various systems in the body. To study their relative contribution to ther LPRs, inhibitors or depletors of mediator systems will be used. Experiments will concentrate on mediators suggested by the medical literature to be of most importance to the LPR. Thus, the effects of cromolyn, corticosteroids, atropine, inhibitors of arachadonic acid metabolism, neutrophil depletion and repletion, platelet depletion, and complement depletion will be studied. 4) Will LPRs in rabbits lead to development of airway hyperreactivity to histamine? The hypotheses include the expectation that parenteral immunization will not lead to airway hyperreactivity while after an LPR, histamine responsiveness will increase and correlate with the inflammation (neutrophil infiltration) produced by the LPR in the airways. This animal model provides a new approach to these four basic questions about LPPs. The results should give insight into the human process, and aid clinical studies attempting to prevent these responses.
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