Adherence of circulating eosinophil to vascular endothelium and their recruitment to extravascular sites in inflamed tissues is the hallmark of allergic inflammation. Recent studies have identified an important role for adhesion molecules and other mediators in the sequestration of eosinophils to sites of inflammation. In this competing renewal we first postulate that vascular cell adhesion molecule (VCAM-1) is a multifunctional cell adhesion molecule that supports initial rolling, activation dependent stable adhesion and chemokine mediated transmigration of eosinophils by interacting with different activation states of alpha4 integrins. Using VCAM-1 deficient heterozygous mice we will determine the tissue specific contribution of VCAM-1 to eosinophil recruitment to sites of allergic inflammation in the skin and peritoneum. Our studies have identified that CD44 may function as a novel rolling receptor for human eosinophils. Furthermore, C3a appears to function as a eosinophil active chemoattractant to mediate stable adhesion of rolling cells. We will therefore, examine the function of CD44 and C3a in eosinophil mediated allergic inflammation. Since matrix matalloproteinases (MMPs) play an important role in the migration of leukocytes within the extravascular space, we will examine the importance of eosinophil expressed MMP-9 as well as an inducible eosinophil-specific MMP, designated as MMP-E, in mediating eosinophil chemotaxis in vivo as part of the second specific aim. In addition monoclonal antibodies against MMP-E will be generated with a view to better understand the biochemical and functional regulation of MMP-E in the context of eosinophil recruitment and allergic inflammation. Since exposure to cytokines such as IL-5 leads to significant eosinophilia, in the third specific aim, the mechanisms of IL-5/allergen-induced mobilization of hematopoietic progenitor/stem cell (HPSC) and eosinophil committed progenitors in the bone marrow will be investigated. We will also investigate how IL-5 modulates the trafficking/migration of HPSC from the bone marrow microenvironment (stromal and endothelial cells) to distal sites of allergic inflammation (lung endothelial cells under conditions of flow. Using in vivo techniques of intravital microscopy along with in vitro molecular and cellular tools, the proposed studies are intended to give a better understanding of the molecular mechanisms mediating eosinophil interactions in inflamed blood vessels and tissues and to provide a basis for developing novel therapeutic strategies for treatment of allergic inflammation.
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