Chronic Allergic Asthma is a serious condition that affects hundreds of thousands of adults and children each year, resulting in time lost from school and work, family and behavior problems, and even many deaths. Chronic allergic asthma is not explained by simple immediate allergic responses which result in airway smooth muscle spasm, but consists of both airway obstruction and airway inflammation in the context of increased airway hyperreactivity. Allergen bronchoprovocation has defined both an early and late asthmatic response (LAR); the LAR best explains features of chronic allergic asthma. This proposal is intended to characterize the late phase response (LPR) in the airways of """"""""allergic"""""""" rabbits which preferentially produce allergen specific IgE as a model of a human LAR. The working hypothesis proposes that the LPR is an inflammatory response to allergen challenge by granule (and matrix)-stored and formed mediators released from mast cells to initiate cellular inflammation, increasd permeability, and increased airway reactivity.
Specific aims i nclude: 1A) to utilize the Pinkard model for the """"""""allergic"""""""" rabbit by immunizing neonatal rabbits on the day of birth and thereafter until the age of three months to preferentially produce allergen specific IgE; 1B) to challenge sensitized rabbits with allergen aerosol and measure dynamic compliance and lung resistance to characterize and early and late phase airway response; 2) to isolate, characterize, and purify neutrophil and eosinophil chemotactic factors from serum and lung lavage fluid using gel filtration and HPLC; 3) to quantitate other mediators of early and LPR including histamine, adenosine, PGD2, and LTC4 in blood and BAL; 4) to quantitate alpha, beta, and cholinergic receptors in peripheral lung tissue by radioligand binding assay; 5) to study histopathology and heterogeneity of lung mast cells and degranulation of eosinophils, neutrophils, and macrophages with light and electron microscopy; 6) to characterize structure-function relationships of tracheal epithelial cells in vivo from immunized rabbits after allergen challenge and in vitro in response to chemotactic and biochemical mediators using light and electron microscopy with freeze-fracture techniques to study molecular permeability and cell transit through tight junctions.
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