Regulation of E-selectin expression in postischemic intestinal microvasculature
Regulation of E-selectin expression in postischemic intestinal microvasculature
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DOI：
10.1152/ajpgi.2000.278.6.g878
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发表时间：
2000-06-01
影响因子：
4.5
通讯作者：
Granger, DN
中科院分区：
文献类型：
--
作者：
Russell, J;Epstein, CJ;Granger, DN
单层培养的内皮细胞暴露在低氧-复氧状态下，E-选择素的表达和E-选择素依赖的中性粒细胞-内皮细胞黏附呈转录依赖性增加。本研究的总体目标是：1)确定缺血再灌注(I/R)是否促进体内E-选择素的上调；2)如果是，确定这种反应的介质；以及3)评估E-选择素在I/R诱导的中性粒细胞募集中的作用。用双标记单抗(MAb)技术检测肠血管E-选择素的表达。完全阻断肠系膜上动脉(30~60min)，再灌流3~24 h，造成缺血。随着缺血时间的延长，E-选择素的表达水平逐渐增加(2~5倍)，峰值出现在缺血45min和再灌注5h后。随后的实验表明，在过量表达铜锌超氧化物歧化酶的转基因小鼠中，I/R诱导的E-选择素表达的增加(在5小时)显著钝化，或者用肿瘤坏死因子(TNF)-α的封闭抗体或核因子-kappa B(NF-kappa B)激活的抑制剂(PS341)处理野生型小鼠。给予E-选择素特异性单抗可显著减少I/R诱导的中性粒细胞在肠道中的募集。这些结果表明，超氧化物和肿瘤坏死因子-α通过一种依赖于核因子-kappaB的机制来介导肠I/R诱导的E-选择素的表达；这种E-选择素的上调在I/R诱导的中性粒细胞募集中起重要作用。
Monolayers of cultured endothelial cells exposed to hypoxia-reoxygenation exhibit a transcription-dependent increase in E-selectin expression and E-selectin-dependent neutrophil-endothelial cell adhesion. The overall objectives of this study were 1) to determine whether ischemia-reperfusion (I/R) promotes upregulation of E-selectin in vivo; 2) if so, to define the mediators of this response; and 3) to assess the contribution of E-selectin to I/R-induced neutrophil recruitment. The dual-radiolabeled monoclonal antibody (MAb) technique was used to measure E-selectin expression in the intestinal vasculature. Ischemia was induced by complete occlusion (30-60 min) of the superior mesenteric artery followed by 3-24 h of reperfusion. Increasing durations of ischemia elicited progressively increasing (2- to 5-fold) levels of E-selectin expression, with the peak response noted after 45 min of ischemia and 5 h of reperfusion. Subsequent experiments revealed that I/R-induced increase in E-selectin expression (at 5 h) is significantly blunted in transgenic mice that overexpress Cu,Zn-superoxide dismutase or by treatment of wild-type mice with either a blocking antibody against tumor necrosis factor (TNF)-alpha or an inhibitor of nuclear factor-kappa B (NF-kappa B) activation (PS341). Administration of an E-selectin-specific MAb dramatically reduced I/R-induced recruitment of neutrophils in the intestine. These findings suggest that superoxide and TNF-alpha mediate gut I/R-induced E-selectin expression via an NF-kappa B-dependent mechanism; this upregulation of E-selectin contributes significantly to I/R-induced neutrophil recruitment.