[unreadable] [unreadable] Exacerbations of asthma are associated with a poor quality of life, a high risk of mortality, and account for a disproportionate cost of asthma care. Preliminary evidence points to a number of specific mechanisms and sites within the air passages that may play critical roles in the pathogenesis of asthma exacerbations. We will focus on the demonstrated associations between disease in the upper (nose & sinuses) and lower airways, and on the ability of fibrin to adversely effect lung function. We hypothesize that exacerbations of asthma reflect a coordinated dysfunction throughout the airway tree, particularly of the upper and large conducting airways, as a consequence of eosinophilic inflammation and fibrin formation. The overall goal of the proposal is to explore specific candidate mechanisms behind an asthma exacerbation, and to establish the extent to which those mechanisms act synergistically to produce a disease that is much worse than the sum of its parts. We propose three specific aims: Specific Aim 1: To determine the contribution and resolution of the central airways to an acute asthma exacerbation; Specific Aim 2: To determine the quantitative and temporal relationships between eosinophilic inflammation and narrowing of the upper and lower airways; Specific Aim 3: To determine how extra-vascular fibrin within the lower airways contributes to the severity of asthma exacerbations. These aims will be addressed in an integrated and comprehensive investigation using case-controlled groups of subjects presenting in the emergency department with acute asthma exacerbations, subjects with stable asthma, and normal controls. We will draw on the complementary expertise of our investigators, our established record of recruiting asthmatic subjects for clinical investigation, and the pathophysiological phenotyping resources at both participating institutions. This research is expected to elucidate the roles played by inflammation and fibrin formation in the airways, which will enhance our current poor understanding of the pathogenesis of asthma exacerbations. Such information may ultimately lead to new therapeutic strategies. (End of Abstract) [unreadable] [unreadable]