Trafficking of eosinophils from the bone marrow to tissues may contribute to tissue damage and remodeling which are features of chronic allergic inflammation in human subjects with severe ongoing allergic inflammation. The mechanism and consequence of eosinophil trafficking to tissues is difficult to study in human subjects. We have therefore developed a novel mouse model of sustained eosinophil trafficking from bone marrow to tissues in response to repetitive allergen challenge which is a model that shares many features with ongoing allergic inflammation in humans. We propose to use this novel mouse model to investigate how eosinophils traffic in angiogenic vessels at sites of allergic inflammation, and once in the tissues contribute to angiogenesis and fibrosis.
Specific aims#1 and #2 will focus on studying the interaction of eosinophils with endothelium in angiogenic vessels in a skin chamber model which allows direct visualization of fluorescently labeled eosinophils in blood vessels in the skin chamber. Eosinophil adhesion in angiogenic vessels and vascular permeability changes will be quantitated in mice treated with neutralizing Abs to VEGF and other angiogenic cytokines identified to be expressed at sites of ongoing allergic inflammation.
In specific aims #3 and #4, we propose to determine the contribution of different isoforms of TGF-beta derived from eosinophils to tissue fibrosis, as well as the importance of fibroblast progenitor trafficking from the bone marrow tissue to tissue fibrosis. Overall these studies will help to determine the role of ongoing allergic inflammation to blood vessel and tissue changes which result in persistent tissue swelling and scarring at sites of ongoing allergic inflammation. These studies may identify potential therapeutic targets which can reduce the tissue damage and swelling at sites of ongoing allergic inflammation in human subjects with severe ongoing allergies. ? ? ?
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