环氧合酶-2在小肠缺血再灌注损伤中对免疫状态的影响

Effect of Cyclooxygenase-2 on Immune Status in Small Bowel Ischemia-reperfusion Injury

背景:小肠缺血再灌注(I/R)是危重症过程中常见的病理改变,研究其损伤发生机制对多器官功能障碍综合征的防治具有重要意义。目的:探讨COX-2在小肠I/R损伤中对免疫状态的影响。方法:48只大鼠随机分为假手术组(n=8)、I/R模型组(n=20)和COX-2选择性抑制剂尼美舒利干预组(n=20),干预组于造模前1 h予尼美舒利80 mg/kg灌胃。各组分别于再灌注3、6、12、24 h后采集标本,行小肠组织COX-2 mRNA、血清D-乳酸、血清促炎(IL-6、TNF-α)和抗炎(IL-10)细胞因子以及全血T细胞亚群检测。结果:I/R模型组小肠组织COX-2 mRNA表达、血清D-乳酸水平在再灌注后3 h即明显增高,6 h时达峰值,各时点均显著高于假手术组(P<0.05),同时血清IL-6、TNF-α、IL-10水平显著增高(P<0.05),全血CD4+/CD8+比值持续降低(P<0.05)。与同时点I/R模型组相比,尼美舒利干预组COX-2 mRNA表达、D-乳酸水平显著降低(P<0.05),IL-10水平、CD4+/CD8+比值显著增高(P<0.05),IL-6、TNF-α水平略有降低。结论:COX-2在小肠I/R损伤中发挥重要作用,其机制可能为改变促炎/抗炎细胞因子之间以及CD4+/CD8+细胞之间的动态平衡,即同时作用于非特异性和特异性免疫系统,导致严重的机体免疫状态紊乱。COX-2选择性抑制剂可能系通过抗炎和免疫调节作用改善小肠I/R损伤。

Background： Small bowel ischemia-reperfusion （I/R） is a common pathological change in critical care medicine, thus it is of great importance to study the underlying mechanism of I/R injury for prevention and management of multiple organ dysfunction syndrome. Aims： To investigate the effect of COX-2 on immune status in small bowel I/R injury. Methods ： Forty-eight rats were randomly divided into three groups ： sham operated group （ n = 8 ） , I/R model group （ n = 20） and nimesulide （a COX-2 selective inhibitor） intervention group （n = 20）. In intervention group, nimesulide 80 mg/ kg was administered intragastrically 1 hour before model construction. Blood and intestinal tissue samples were obtained 3, 6, 12 and 24 hours, respectively, after reperfusion. COX-2 mRNA in intestinal tissues, as well as serum D-lactic acid, serum proinflammatory （IL-6 and TNF-a） and anti-inflammatory cytokines （IL-10） , and whole blood T cell subsets were measured. Results ： In I/R model group, increase of intestinal COX-2 mRNA and serum D-lactic acid initiated at the early stage of reperfusion （3 h） and reached the peak at 6 h, and at all time points were significantly higher than those in sham operated group （ P 〈 0.05 ） ; serum IL-6, TNF-a and IL-10 increased simultaneously （ P 〈 0.05 ） , and whole blood CD4＋/CD8＋ ratio decreased continuously （ P 〈 0.05 ）. When compared with I/R model group at the same time point, COX-2 mRNA and D-lactic acid decreased significantly （ P 〈 0. 05 ） and IL-10 and CD4＋/CD8＋ ratio increased significantly （ P 〈 0.05 ） in nimesulide intervention group ; IL-6 and TNF-a in intervention group only had a little decrease. Conclusions： COX-2 might play an important role in small bowel I/R injury by altering the dynamic equilibrium between pro-/anti-inflammatory cytokines and CD4＋/CD8＋ cells, in other words, by affecting nonspecific and specific immunity simultaneously, ultimately leading to severe immunological disorder. COX-2 selective inhibitor can attenuate small bowel I/R injury through its antiinflammatory and immunomodulatory effects.