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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055030-07
Application #
7285567
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
May, Michael K
Project Start
1999-08-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
7
Fiscal Year
2007
Total Cost
$190,059
Indirect Cost
Name
University of Louisville
Department
Physiology
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Wei, Xiaoli; Song, Ming; Yin, Xinmin et al. (2015) Effects of Dietary Different Doses of Copper and High Fructose Feeding on Rat Fecal Metabolome. J Proteome Res 14:4050-8
Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang et al. (2015) Kupffer cell depletion protects against the steatosis, but not the liver damage, induced by marginal-copper, high-fructose diet in male rats. Am J Physiol Gastrointest Liver Physiol 308:G934-45
Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang et al. (2013) Modest fructose beverage intake causes liver injury and fat accumulation in marginal copper deficient rats. Obesity (Silver Spring) 21:1669-75
Song, Ming; Schuschke, Dale A; Zhou, Zhanxiang et al. (2012) High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver. J Hepatol 56:433-40
Sakai, Nozomu; Shin, Thomas; Schuster, Rebecca et al. (2011) Marginal copper deficiency increases liver neutrophil accumulation after ischemia/reperfusion in rats. Biol Trace Elem Res 142:47-54
Schuschke, Dale A; Adeagbo, Ayotunde S O; Patibandla, Phani K et al. (2009) Cyclooxygenase-2 is upregulated in copper-deficient rats. Inflammation 32:333-9
Falcone, Jeff C; Lominadze, David; Johnson, W Thomas et al. (2008) Endothelial cell-derived nitric oxide mobilization is attenuated in copper-deficient rats. Appl Physiol Nutr Metab 33:1073-8
Saari, Jack T; Wold, Loren E; Duan, Jinhong et al. (2007) Cardiac nitric oxide synthases are elevated in dietary copper deficiency. J Nutr Biochem 18:443-8
Gordon, Sharon A; Lominadze, David; Saari, Jack T et al. (2005) Impaired deformability of copper-deficient neutrophils. Exp Biol Med (Maywood) 230:543-8
Lominadze, David; Saari, Jack T; Percival, Susan S et al. (2004) Proinflammatory effects of copper deficiency on neutrophils and lung endothelial cells. Immunol Cell Biol 82:231-8

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