Asthma is characterized by chronic IgE dependent airway inflammation, increased airway reactivity and periodic exacerbations of disease. Inhalation of allergen (an IgE mediated acquired immune stimulus), LPS and O3 (innate stimuli) can induce acute exacerbation of asthma, with increases in eosinophils, airway reactivity and decreased lung function. We have observed that O3 and LPS enhance response to allergen, and allergen challenge appears to modify response to O3 and LPS, suggesting interactions between innate and acquired immunity mediate asthma exacerbation. In development of our models of asthma exacerbation, we have focused on inflammation, spirometry and airway reactivity (which is based on spirometric endpoints). However, asthma exacerbation also involves mucus secretion, mucus plugging and impairment of mucociliary clearance (MCC). Our group has developed MCC assessment techniques and we are eager to incorporate this measure into studies of asthma exacerbation to improve understanding of the relationship between inflammatory stimuli, inflammatory cells and function of the human airway. We will test the hypotheses that acquired IgE induced inflammation modifies response to innate stimulation, that innate inflammation enhances antigen presentation and IgE response elements and that CD11b (which we have found correlates very well with changes in lung function as well as granulocyte influx) predicts severity of exacerbation as defined by inflammation, reactivity and MCC. We will pursue the following specific aims: SA1: We will test the hypothesis that doses of endotoxin known to upregulate co-stimulatory molecules on airway macrophages will enhance IgE mediated response to inhaled allergen; SA2: We will test the hypothesis that the innate immune stimulus O3 increases risk for IgE mediated asthma exacerbation and identify potential targets for intervention; SA3: To test the hypothesis that IgE modulates O3 mediated asthma exacerbation by comparing the responses of atopic asthmatics treated with anti-IgE (omalizumab) and placebo to O3 challenge.
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