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大鼠肾缺血再灌注损伤后p38丝裂原活化蛋白激酶的活化及氧自由基清除剂对其的影响
刘文军1,2,贾一韬1,夏照帆1*,付晋凤2,马兵1,吕开阳1,卫伟1
0
(1.第二军医大学长海医院烧伤科,上海 200433; 2.昆明医学院第二附属医院烧伤科,昆明 650101)
摘要:
目的:观察肾缺血再灌注损伤后p38活化的情况,并探讨应用氧自由基清除剂tempol后对其的影响。方法:雄性SD大鼠随机分为假手术组(n=10)、缺血再灌注损伤组(IRI,n=45)和tempol预处理组(n=10)。IRI组采用右侧肾摘除左肾蒂夹闭50 min后松开制备缺血再灌注模型,分别于再灌注0、5、10、15、30、45 min及1、2 h处死动物取肾组织,Western印迹法观察p38活化情况。Tempol处理组动物同样制备缺血再灌注模型,术前1 h尾静脉注射tempol(100 mg/kg),再灌注45 min取肾组织;假手术组行右侧肾摘除但不夹闭左肾蒂,术后45 min取肾组织。Western印迹法观察3组p38活化情况,分析肾组织丙二醛(MDA)含量,ELISA法检测肾组织肿瘤坏死因子α(TNFα)、白细胞介素1β(IL1β)的含量。结果:大鼠肾组织磷酸化p38含量在再灌注早期(5 min)开始升高,45 min达到高峰,再灌注2 h仍较高(P<0.05)。与假手术组相比,IRI和tempol预处理组磷酸化p38含量明显升高(0.103±0.008 vs 2.025±0.136 vs 0.833±0.191,P<0.05),且tempol预处理组低于IRI组(P<0.05)。3组间肾组织MDA、TNFα、IL1β的含量检测结果与磷酸化p38结果类似(P<0.05)。结论:氧自由基介导的p38磷酸化在缺血再灌注引起的大鼠肾脏炎症性损害中具有重要作用;应用tempol可以抑制p38磷酸化,防治缺血再灌注损伤。
关键词:    再灌注损伤  p38丝裂原活化蛋白激酶类  氮氧化物  自由基清除剂  活性氧
DOI:10.3724/SP.J.1008.2008.00167
投稿时间:2007-07-17
基金项目:上海市医学重点学科建设基金(05Ⅲ007).
Effect of tempol, a free radical scavenger, on p38 activation in rats with renal ischemia reperfusion injury
LIU Wen-jun1,2,JIA Yi-tao1,XIA Zhaofan1*,FU Jin-feng2,MA Bing1,LV Kai-yang1,WEI Wei1
(1.Department of Burns,Changhai Hospital,Second Military Medical University,Shanghai 200433,China; 2.Department of Burns,Second Affiliated Hospital of Kunming Medical College,Kunming 650101)
Abstract:
Objective:To investigate the activation of p38 signaling transduction cascade in renal ischemia reperfusion injury(IRI) and to study the effect of tempol, a free oxygen radical scavenger, on p38 activation. Methods:Male SpragueDawley rats were randomly divided into shamoperation group (n=10), IRI group (n=45) and IRI + tempol group(n=10). Animal IRI model was created by renal pedicle ligation (50 min) of the left kidney along with a contralateral nephrectomy followed by 2 h reperfusion. Rats were sacrificed on 0, 5, 10, 15, 30, 45 min, 1 and 2 h after renal reperfusion. Animals in IRI + tempol group were pretreated with tempol (100 mg/kg) 1 h before undergoing the same protocol as in IRI group; the kidney was harvested after 45 min of reperfusion. Animals in the shamoperation group were subjected to contralateral nephrectomy without renal pedicle ligation and were sacrificed 45 min later. The renal p38 activities of the 3 groups were determined by Western blotting analysis. Malondialdehyde (MDA) content was detected and proinflammatory cytokine TNFα, IL1β levels were analyzed by ELISA. Results: Activation of p38 was observed in the kidney as early as 5 min after reperfusion and reached its peak 45 min after reperfusion and remained to be activated until 2 h after reperfusion(P<0.05). The activities of renal p38 in IRI and IRI + tempol group were markedly increased compared with that of the shamoperation group(both P<0.05). Pretreatment with tempol significantly inhibited IRIinduced p38 activation(P<0.05); it also decreased MDA activity and TNFα and IL1β levels (both P<0.05). Conclusion:Our results demonstrate that reactive oxygen speciesmediated p38 activation plays an essential role in IRIinduced renal inflammatory damage in rats, suggesting that inhibition of p38 activation by tempol may be used for prophylaxis and treatment of IRI.
Key words:  kidney  reperfusion injury  p38 mitogen activated protein kinases  N oxides  free radical scavengers  reactive oxygen species