Brief murine myocardial I/R induces chemokines in a TNF-α-independent manner:: role of oxygen radicals
Brief murine myocardial I/R induces chemokines in a TNF-α-independent manner:: role of oxygen radicals
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DOI：
10.1152/ajpheart.2001.281.6.h2549
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发表时间：
2001-12-01
影响因子：
4.8
通讯作者：
Entman, ML
中科院分区：
文献类型：
--
作者：
Nossuli, TO;Frangogiannis, NG;Entman, ML
早期趋化因子在缺血再灌注(I/R)心肌危险区域的诱导首先见于静脉内皮细胞。再灌注与多种诱导机制有关，包括细胞外肿瘤坏死因子(TNF)-α的升高、活性氧中间体(ROI)的形成以及白细胞与静脉内皮细胞的黏附。为了验证ROI能够以非肿瘤坏死因子依赖的方式在心脏小静脉中诱导趋化因子的假设，并且在没有白细胞聚集的情况下，我们利用野生型(WT)和肿瘤坏死因子-α双受体敲除小鼠(DKO)在闭合胸小鼠心肌缺血(15min)和再灌注(3h)的模型中，其中没有梗塞。我们证明，单个短暂的I/R诱导趋化因子巨噬细胞炎症蛋白(MIP)-1α、-1β和-2在mRNA和蛋白水平上显著上调。这种诱导不依赖于肿瘤坏死因子-α，而这些趋化因子的水平在WT和DKO小鼠中都增加了。趋化因子的诱导主要见于小静脉内皮细胞，并伴有核因子-kappaB和c-jun(AP-1)在小静脉内皮细胞的核转位。氧自由基清除剂N-2-巯基丙酰甘氨酸(MPG)在缺血前15min开始静脉滴注，并持续至再灌流期间，可阻止趋化因子的诱导，但再灌流开始后给予MPG则无作用。结果表明，在无梗死或不可逆细胞损伤的情况下，再灌流心肌中ROI的产生可迅速诱导静脉内皮细胞中的C-C和C-X-C趋化因子。
Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-alpha, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-alpha -independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-alpha double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1 alpha,-1 beta, and -2 at both the mRNA and protein levels. This induction was independent of TNF-alpha, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-kappaB and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.