Central to the pathogenesis of allergic diseases are both the recruitment and activation of eosinophils at sites of allergic inflammation. Among mediators pertinent to allergic inflammation, eosinophils are sources of eicosanoids, including cysteinyl leukotrienes. Cysteinyl leukotrienes are both major paracrine mediators of allergic inflammation and, as only recently recognized, autocrine intracellular mediators regulating vesicular transport-mediated release of cytokines, including the allergic disease pertinent cytokine, IL-4, from eosinophil granule stores. Eosinophils and other leukocytes associated in vivo with inflammatory reactions: l) exhibit, as yet poorly understood, """"""""priming"""""""" responses, by which these leukocytes respond more prominently to agonists and can generate greater quantities of eicosanoids; and 2) characteristically contain increased numbers of intracellular lipid bodies. In vitro studies have indicated that lipid bodies are highly regulated, inducible organelles and are sites involved in the priming responses for heightened eicosanoid formation by eosinophils and other cells. Although lipid bodies are ubiquitous in eosinophils and leukocytes in vivo associated with inflammation, the formation and function of lipid bodies within eosinophils in vivo in sites of allergic inflammation have never been investigated. The proposed studies will utilize well- established in vivo models of allergic inflammation to investigate mechanisms of eosinophil activation and to test the hypothesis that intracellular lipid body formation is centrally involved in eosinophil activation in inflammatory responses. Studies will investigate eosinophil lipid body formation and functioning in vivo in allergic inflammation, with four specific aims: 1) investigate molecular pathways of eosinophil lipid body formation in murine models of allergic inflammation; 2) characterize inflammation pertinent components of in vivo-elicited murine eosinophil lipid bodies; 3) evaluate functional roles of lipid bodies in eicosanoid generation and autocrine and paracrine signaling in murine eosinophils; and 4) evaluate pathways of lipid body formation as targets for anti-inflammatory/anti- allergic drug development, including specifically investigating the effects of Brazilian rain forest plant-derived bioactive products on lipid body formation and eicosanoid generation. These studies aim to provide new insights into fundamental intracellular mechanisms of eosinophil activation and potentially identify novel anti-inflammatory therapeutic targets. These studies, to be performed in Brazil, will utilize the expertise of Brazilian investigators with in vivo models of allergic inflammation to extend in vitro studies of human eosinophils in NIH grant # RO1 AI20241.
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