Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-α
Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-α
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DOI：
10.1189/jlb.0706480
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Cuzzocrea, Salvatore
中科院分区：
文献类型：
--
作者：
Esposito, Emanuela;Mazzon, Emanuela;Cuzzocrea, Salvatore
在本研究中，我们使用tnf - α受体1敲除（tnf - α R1KO）小鼠来评估TNF-a在多脏器缺血再灌注损伤发病机制中的可能作用。将小鼠肠系膜上动脉和腹腔动脉夹持30min后进行再灌注，诱导小鼠缺血再灌注损伤。再灌注60分钟后处死动物进行组织学检查和生化研究。损伤野生型（WT）小鼠回肠tnf - α水平、髓过氧化物酶活性显著升高，组织学损伤和细胞凋亡明显。多脏器缺血再灌注损伤也与死亡率显著相关。WT损伤小鼠回肠再灌注切片显示p -选择素、VCAM、ICAM-1和e -选择素阳性染色。tnf - α R1KO损伤小鼠组织切片中p -选择素、e -选择素、VCAM和ICAM-1的表达强度和程度均明显降低。缺血再灌注损伤的tnf - α R1KO小鼠也显示出中性粒细胞进入肠道的显著减少，细胞凋亡减少，肠道组织学状态改善，生存率提高。此外，我们还研究了依那西普（一种tnf - α可溶性受体构建物）对多脏器缺血再灌注损伤的影响。依那西普（5mg /kg，再灌注前5min ig）可显著降低炎症反应和回肠损伤。综上所述，我们的研究结果清楚地证明了TNF-a在缺血再灌注损伤中起着重要作用，并提出了调节tnf - α表达可能是一种新的可能策略的假设。
In the present study, we used TNF-alpha receptor 1 knockout (TNF-alpha R1KO) mice to evaluate a possible role of TNF-a on the pathogenesis of ischemia and reperfusion injury of the mudtivisceral organs. Ischemia and reperfusion injury was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were killed for histological examination and biochemical studies. Injured wildtype (WT) mice developed a significant increase of ileum TNF-alpha levels, myeloperoxidase activity, and marked histological injury and apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with a significant mortality. Reperfused ileum sections from injured WT mice showed positive staining for P-selectin, VCAM, ICAM-1, and E-selectin. The intensity and degree of P-selectin, E-selectin, VCAM, and ICAM-1 were reduced markedly in tissue sections from injured TNF-alpha R1KO mice. Ischemia and reperfusion-injured TNF-alpha R1KO mice also showed a significant reduction of neutrophil infiltration into the intestine, a reduction of apoptosis, an improved histological status of the intestine, and survival. In addition, we investigated the effect of Etanercept, a TNF-alpha soluble receptor construct, on ischemia and reperfusion injury of the multivisceral organs. Etanercept (5 mg/kg administered i.p. 5 min prior to reperfusion) significantly reduced the inflammatory response and the ileum injury. Taken together, our results clearly demonstrate that TNF-a plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of TNF-alpha expression may represent a novel and possible strategy.