Eosinophilic inflammation is a prominent feature of airway inflammation associated with asthma. This application seeks to improve our understanding of the molecular mechanisms of eosinophil recruitment in vivo as well as understand the consequence of chronic eosinophilic inflammation on airway structure and function. The recruitment of flowing eosinophils out of inflamed blood vessels in vivo shares many features with other circulating leukocytes such as neutrophils, but also has distinct features, which allow for the selective migration of eosinophils into sites of allergic inflammation. In this application we will focus on increasing our understanding of the selective and common pathways used by eosinophils to migrate out of inflamed blood vessels. Studies of eosinophil trafficking will focus on increasing our understanding of three important steps in eosinophil adhesion to endothelium and transmigration across endothelium in vivo, namely the role of sialic acid containing carbohydrates in mediating eosinophil adhesion to endothelium, the role of GI protein coupled receptors (CCR-3 and PAF receptors) in mediating activation dependent adhesion of eosinophils in vivo, and the role of PECAM in mediating eosinophil transmigration across endothelium. The adhesion studies will utilize innovative methods to study adhesion in vitro (single cell adhesion assay) and intravital microscopy studies to visualize fluorescently labeled eosinophil trafficking in vivo. The consequence of chronic eosinophilic inflammation on airway remodeling and on airway responsiveness to methacholine will be studied in wild type mice and compared to mice deficient in eosinophils (IL-5 deficient mice). Overall, these studies should improve our understanding of the molecular mechanism of eosinophil recruitment in vivo and its effect on airway structure and function.
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