LEUKOCYTE ADHESION IN COPPER DEFICIENT MICROCIRCULATION

University Of Louisville, Louisville KY

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Abstract

DESCRIPTION (provided by applicant): Regulation of the microvascular response to inflammatory stimuli is highly dependent upon the interactions between neutrophils and the endothelium. We have shown a significant role for dietary copper in various endothelial interactions in the inflammatory process, including nitric oxide (NO)-mediated vasodilation, macromolecular leakage, and thrombosis. Recently, we have studied the role of dietary copper in microvascular control mechanisms with an emphasis on leukocyte/endothelial adhesion. We have demonstrated that dietary copper restriction causes tissue-specific changes in neutrophil/endothelial adhesion and transmigration. Neutrophil accumulation, the expression of the adhesion molecule ICAM-1 and the transcription factor NF-kappaB are all greater in the lungs of copper-deficient rats compared to copper-adequate controls. Based on these results, we hypothesize that dietary copper deficiency has a priming effect on leukocytes and pulmonary vascular endothelial ceils such that the lung becomes hypersensitive to inflammatory stimuli and more susceptible to the development of acute lung injury. Therefore the specific aims of this study are to: 1) determine the role of dietary copper in leukocyte/endothelial cell interactions in the lung microcirculation; 2) determine the mechanisms by which copper deficiency primes cells for acute inflammation and 3) determine at what concentration of dietary copper the inflammatory mechanisms become enhanced in the in vivo animal microcirculation. Aim #1 will use both in vivo and in vitro models of the lung microcirculation to study leukocyte/endothelial cell adhesion and chemotaxis. Aim #2 will study the role of copper in the NF-kB signaling pathway and in neutrophil priming. Aim #3 will examine these mechanisms under conditions of copper-marginal diets. These experiments have particular relevance since analysis of typical Western diets suggest that 1/3 to 1/2 of those diets may provide less than the RDA of 900mg Cu/day.