Protective effect of alpha-lipoic acid in lipopolysaccharide-induced endothelial fractalkine expression

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Fractalkine is a unique chemokine that functions as a chemoattractant as well as an adhesion molecule on endothelial cells activated by proinflammatory cytokines. Alpha-lipoic acid ( LA), a naturally occurring dithiol compound, is an essential cofactor for mitochondrial bioenergetic enzymes. LA improves glycemic control, reduces diabetic polyneuropathies, and mitigates toxicity associated with heavy metal poisoning. The effects of LA on processes associated with sepsis, however, are unknown. We evaluated the antiinflammatory effect of LA on fractalkine expression in a lipopolysaccharide-induced endotoxemia model. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-alpha- or IL-1 beta-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-kappa B and specificity protein-1. LA also decreased TNF-alpha- or IL-1 beta-stimulated monocyte adhesion to human umbilical vein endothelial cells. As shown by immunohistochemistry, fractalkine protein expression was markedly increased by treatment with lipopolysaccharide in arterial endothelial cells, endocardium, and endothelium of intestinal villi. LA suppressed lipopolysaccharide-induced fractalkine protein expression and infiltration of endothelin 1-positive cells into the heart and intestine in vivo. LA protected against lipopolysaccharide-induced myocardial dysfunction and improved survival in lipopolysaccharide-induced endotoxemia. These results suggest that LA could be an effective agent to reduce fractalkine-mediated inflammatory processes in endotoxemia.
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Issue Date
2005-10
Language
English
Article Type
Article
Keywords

NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; TNF-ALPHA; CELL-ADHESION; VASCULAR BIOLOGY; SEPTIC SHOCK; E-SELECTIN; RAT; ACTIVATION; SEPSIS

Citation

CIRCULATION RESEARCH, v.97, no.9, pp.880 - 890

ISSN
0009-7330
DOI
10.1161/01.RES.0000186522.89544.4D
URI
http://hdl.handle.net/10203/92828
Appears in Collection
MSE-Journal Papers(저널논문)
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