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p38丝裂原活化蛋白激酶在小鼠胃缺血-再灌注损伤中的作用
王建明1,2,郑德义1,2,贾一韬1,付晋凤2,郑兴锋1,吕开阳1,夏照帆1*
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(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:

目的探讨p38丝裂原活化蛋白激酶(p38 MAPK）在小鼠胃缺血再灌注损伤中的作用。方法C57BL/6小鼠随机分为3组：假手术组、模型组和CNI1493预处理组,CNI1493预处理组于术前1 h腹腔注射p38 MAPK 抑制剂CNI1493(2 mg/ml）溶液10 ml/kg。通过夹闭小鼠腹腔动脉30 min后松开动脉夹再灌注1 h制作胃缺血再灌注损伤模型。再灌注1 h后取胃标本,甲醛固定后铺平拍照,计算胃黏膜出血面积百分比。应用蛋白质印迹法检测并比较各组磷酸化及总p38、JNK、ERK,磷酸化NFκB p65以及分裂型Caspase3 的表达水平。结果与假手术组比较,模型组胃黏膜出血面积明显增大(P<0.05）,p38、JNK以及ERK明显激活(P<0.05）,磷酸化NFκB p65以及促凋亡蛋白激活型Caspase3表达明显增多(P<0.05）。CNI-1493预处理能明显逆转上述改变(P<0.05）。结论MAPK/NFκB通路活化在胃缺血再灌注损伤中起到重要作用,p38 MAPK抑制剂CNI1493能抑制MAPK/NFκB通路活化、减少凋亡蛋白表达,减轻胃缺血再灌注引起的黏膜出血。

关键词: 胃再灌注丝裂原活化蛋白激酶 NF-κB 细胞凋亡

DOI：10.3724/SP.J.1008.2010.0250

投稿时间：2009-12-13修订日期：2010-01-14

基金项目:国家自然科学基金重点项目(30730091).

Role of p38 MAPK in ischemia/reperfusion induced gastric injury in mice

WANG Jian-ming1,2, ZHENG De-yi1,2, JIA Yi-tao1, FU Jin-feng2, ZHENG Xing-feng1, L Kai-yang1, XIA Zhao-fan1*

(1.Department of Burns, Changhai Hospital, Second Military Medical University, Shanghai 200433, China;2.Department of Burns, The Second Affiliated Hospital of Kunming Medical College, Kunming 650101, Yunnan, China)

Abstract:

ObjectiveTo investigate the role of p38 MAPK on gastric ischemia/reperfusion (I/R)induced injury in mice.MethodsC57BL/6 mice were randomly divided into three groups: sham+vehicle group, I/R+vehicle group (as control), and I/R+CNI1493 group. The gastric IR injury mice were prepared by occluding the celiac artery for 30 min followed by reperfusion for 1 h. Shamoperated animals underwent the same surgical procedure without clamping. Physiological saline (0.9% NaCl, 10 ml/kg) or CNI1493(a p38 MAPK inhibitor, 10 ml/kg, 2 mg/ml) was intraperitoneally administered 1 h before ischemia. A picture of the whole stomach was obtained after fixation with formalin, and the bleeding area in the whole stomach was obtained by a digital imaging analyzer (Image J 1.4. NIH). The levels of phospho and totalmitogenactivated protein kinases (MAPKs including p38, JNK, and ERK), phosphonuclear factorκB (NFκB) and cleaved Caspase3 in the injured stomach tissue were determined by Western blotting analysis.ResultsCompared with sham+vehicle group, I/R group had markedly larger gastric bleeding area (P<0.05), activated p38, JNK, and ERK (P<0.05), and markedly increased NFκB p65 and cleaved Caspase3 expression (P<0.05). Pretreatment with CNI1493 significantly inhibited the above changes in I/R group (P<0.05). ConclusionActivation of MAPK/NFκB pathway play a very important role in I/Rinduced gastric injury. Pretreatment with p38 MAPK inhibitor, CNI1493, can inhibit MAPK/NFκB pathway, decrease expression of apoptosis protein expression, and reduce gastric mucosal bleeding.

Key words: stomach reperfusion injury mitogen activated protein kinase NF κB apoptosis