Sung Mi Jeong, Kim Won, Ahn So Young, Cho Chung-Hyun, Koh Gou Young, Moon Sang-Ok, Kim Duk Hoon, Lee Sik, Kang Kyung Pyo, Jang Kyu Yun, Park Sung Kwang
Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, 560-180, Korea.
Circ Res. 2005 Oct 28;97(9):880-90. doi: 10.1161/01.RES.0000186522.89544.4D. Epub 2005 Sep 15.
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-1beta (IL-1beta) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-alpha- or IL-1beta-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-kappaB and specificity protein-1. LA also decreased TNF-alpha- or IL-1beta-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.
趋化因子是一种独特的趋化因子，它既作为趋化剂发挥作用，又作为由促炎细胞因子激活的内皮细胞上的黏附分子。α-硫辛酸（LA）是一种天然存在的二硫醇化合物，是线粒体生物能量酶的必需辅助因子。LA可改善血糖控制、减轻糖尿病多发性神经病变，并减轻与重金属中毒相关的毒性。然而，LA对脓毒症相关过程的影响尚不清楚。我们在脂多糖诱导的内毒素血症模型中评估了LA对趋化因子表达的抗炎作用。肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）显著诱导内皮细胞中趋化因子mRNA和蛋白表达。LA通过抑制核因子-κB和特异性蛋白-1的活性，强烈抑制TNF-α或IL-1β诱导的内皮细胞趋化因子表达。LA还减少了TNF-α或IL-1β刺激的单核细胞与人脐静脉内皮细胞的黏附。免疫组织化学显示，脂多糖处理后，动脉内皮细胞、心内膜和肠绒毛内皮中趋化因子蛋白表达明显增加。LA在体内抑制脂多糖诱导的趋化因子蛋白表达以及内皮素1阳性细胞向心脏和肠道的浸润。LA可预防脂多糖诱导的心肌功能障碍，并提高脂多糖诱导的内毒素血症的存活率。这些结果表明，LA可能是一种有效的药物，可减少内毒素血症中趋化因子介导的炎症过程。
