U50488H对感染性休克大鼠细胞因子的影响

Effects of U50488H on cytokines in septic shock rats

目的 观察κ-阿片受体激动剂(U50488H)对感染性休克大鼠细胞因子的影响.方法 选取健康雄性SD大鼠40只,按照随机数字表法分为假手术组、感染性休克组、U50488H+感染性休克组、nor-BNI+ U50488H+感染性休克组和nor-BNI+感染性休克组(每组n=8).假手术组仅行腹腔正中切开、腹腔探查、翻动盲肠后关腹;感染性休克组采用盲肠结扎穿孔术(CLP)建立大鼠感染性休克模型;U50488H+感染性休克组在休克即刻静脉注射U50488H,余同感染性休克组;nor-BNI+ U50488H+感染性休克组在关闭腹腔后3.5h静脉注射κ-阿片受体特异性拮抗剂(nor-BNI),余同U50488H+感染性休克组;nor-BNI+感染性休克组不静脉注射U50488H,余同nor-BNI+ U50488H+感染性休克组.各组大鼠分别于关闭腹腔时及术后3、6、12h时留取血样,检测中心静脉血氧饱和度(ScvO2)、血乳酸水平(Lac);外周血中性粒细胞比例;检测血清中细胞因子[肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)和血管内皮细胞黏附分子(VCAM)]、血清酶学[乳酸脱氢酶(LDH)和超氧化物歧化酶(SOD)的水平.另取30只大鼠分别构建假手术组、感染性休克组、U50488H+感染性休克组大鼠模型(每组n=10),用于观察24 h存活率.结果 与假手术组比较,感染性休克组大鼠术后3、6、12 h ScvO2明显下降(P<0.01),中性粒细胞比例明显升高(P<0.01),血Lac、TNF-α、IL-1β、IL-6和VCAM等细胞因子水平明显升高(P<0.01),IL-10水平明显下降(P<0.01),LDH水平明显升高(P<0.01),SOD水平明显下降(P<0.01).与感染性休克组比较,U50488H+感染性休克组大鼠术后3、6、12 h ScvO2无明显变化(P>0.05);而外周血中性粒细胞比例明显著下降(P<0.01),血Lac、TNF-α、IL-1β、IL-6和VCAM等细胞因子水平明显降低(P <0.01,P<0.05),IL-10水平明显升高(P<0.01),LDH水平明显下降(P<0.01),SOD水平明显回升(P<0.01).U50488H的上述效应可被κ--阿片受体阻断剂nor-BNI所阻断(P<0.01).U50488H+感染性休克组大鼠存活率高于感染性休克组(P<0.05).结论 U50488H能通过κ-阿片受体介导,明显改善感染性休克大鼠组织灌注,抑制炎症反应,减轻组织损伤,增强机体抗氧化能力和降低病死率.

Objective To investigate the effects of U50488H on cytokines in septic shock rats and explore its protective mechanisms. Methods Forty male Sprague-Dawley rats were randomly divided into four gioups ( n = 8): sham group, septic shock group, U50488H + septic shock group, nor-BNI + U50488H + septic shock group and nor-BNI + septic shock group, with 8 rats in each group. In sham group, only open-close abdomen was performed. Cecal ligation and puncture ( CLP) was performed to induce septic shock in septic shock group. Rats of U50488H + septic shock group were treated with U50488H injection intravenously at the shock point, and other procedures were the same as the septic shock group. Rats of nor-BNI + U50488H + septic shock group were treated with nor-BNI injection intravenously 3.5 h after abdomen closed, and other procedures were the same as U50488H +septic shock group. Except for U50488H injection, the rats of the nor 一 BNI + septic shock group received procedures the same as nor 一 BNI + U50488H + septic shock group. Central vena cava oxygen saturation ( ScvO2 ), lactate ( Lac ), proportion of peripheral neutrophilic granulocyte, tumor necrosis factor-α(TNF -α), interleukin 1β(IL - 1β), interleukin-6 (IL - 6 ), interleukin-10 (IL - 10), vascular cell adhesion molecule ( VCAM ), lactate dehydrogenase ( LDH ) and superoxide dismutase ( SOD) in serum were measured at-abdomen closed, 3 , 6, 12 hours after CLP. Another 30 rats were randomly divided into three groups ( n = 10 ): sham group, septic shock group, U50488H + septic shock group. And the survivals of 24 h were evaluated. Results After 3 , 6, 12 hours of CLP, the ScvO2 , IL-10 and SOD in serum of the septic shock group were lower than that of the control group (P <0. 01), while the proportion of peripheral neutrophilic granulocyte, Lac, TNF -α, IL - 1 β, IL - 6, VCAM and LDH were higher (P <0. 01 ). The differences of ScvO2 in the septic shock group and U50488H septic shock group were not statistically significant. Compared with septic shock group, the levels of the proportion of peripheral neutrophilic granulocyte, Lac, TNF -α, IL - lβ, IL -6, VCAM and LDH of the U50488H+septic shock group decreased (P <0.01 , P<0. 05), whereas the levels of IL - 10 and SOD in serum increased significantly (P <0. 01 ). Moreover, the above effects of U50488H were pretreatment abolished by nor-BNI ( a selective κ-opioid receptor antagonist)( P <0.01 ). The survival rate of 24 h in U50488H+septic shock group was higher than that of septic shock group (P < 0.05). Conclusion U50488H has protective effects on rats with septic shock by improving tissue perfusion, inhibiting inflammation, reducing tissue damage, enhancing the anti 一 oxidation capacity, and can lower the mortality rate.