依达拉奉对重症急性胰腺炎大鼠肠黏膜屏障功能障碍的保护作用
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摘要
目的：探讨应用依达拉奉对重症急性胰腺炎大鼠肠黏膜屏障功能损伤的保护作用及其机制,从而为临床防治重症急性胰腺炎肠黏膜屏障功能障碍提供参考依据。
方法：60只清洁级SD大鼠随机分为正常组(Norm组)(n=6)、假手术组(Sham组)(n=18)、重症急性胰腺炎组(SAP组)(n=18)和依达拉奉治疗组(ED组)(n=18)。Norm组不做任何处理；Sham组在开腹后仅翻动胰腺后关腹；SAP组采用逆行十二指肠胰胆管注射5%牛黄胆酸钠溶液制备SAP大鼠模型；ED组模型制备成功后即刻经尾静脉注射3mg/kg的依达拉奉。分别在建模成功后6h、12h、24h采集血液、肠道、胰腺标本。检测各组不同时间点血浆二胺氧化酶(DAO),血淀粉酶,及肠道组织中的丙二醛(MDA),超氧化物歧化酶(SOD),细胞间黏附分子-1(ICAM-1)水平,并且光镜观察肠道及胰腺病理形态的改变。采用SPSS13.0统计软件。Kolmogorow-Smirnow法对各组数据进行正态性检验,符合正态分布则用均数±标准差(x±s)描述,用单因素方差分析(one-way ANOVA分析)行组间差异比较,若各组间差异有统计学意义,进一步用SNK法(q检验)进行两两间比较,采用Pearson相关分析方法进行相关分析。
结果：1.Norm组与Sham组血浆DAO水平差别无统计学意义(P>0.05)；SAP组大鼠术后6h,12h,24h血浆DAO浓度和血淀粉酶浓度均高于Norm组和Sham组(P<0.05)；ED组血浆DAO浓度和血淀粉酶浓度较Norm组和Sham组升高(P<0.05),但较SAP组降低(P<0.05)。2.Norm组与Sham组肠道组织MDA,SOD水平差别无统计学意义(P>0.05)；与Norm组及Sham组相比,SAP组MDA水平3个时间点依次升高(P<0.05)；SOD活性3个时间点依次下降(P<0.05)；ED组较SAP组MDA水平均明显降低,SOD活性明显升高(P<0.05)。3.Nrom组与Sham组肠道组织ICAM-1水平差别无统计学意义(P>0.05)；与Nrom组及Sham组相比,SAP组肠道ICAM-1水平在3个时间点均明显升高(P<0.05)；ED组肠道ICAM-1水平较SAP组下降(P<0.05),但仍高于Nrom组和Sham组(P<0.05)。4.SAP组肠道组织病理学改变包括绒毛,固有层脱落,裸露,黏膜下毛细血管充血；胰腺组织病理学改变包括严重的水肿,出血,坏死,炎症细胞浸润;Norm组和Sham组胰腺及肠道评分差别无统计学意义(P>0.05)；SAP组肠道和胰腺组织损伤病理评分明显高于Nrom组和Sham组(P<0.05)；ED组肠道组织损伤病理评分较SAP组无统计学意义(P>0.05),但仍高于Nrom组和Sham组(P<0.05)；ED组胰腺组织损伤病理评分较SAP组低(P<0.05),但仍高于Nrom组和Sham组(P<0.05)。5.血浆DAO水平与肠道MDA水平呈明显正相关(P<0.01),与肠道SOD活性呈明显负相关(P<0.01)；血浆DAO与肠道组织ICAM-1水平呈明显正相关(P<0.01)。
结论：SAP早期即存在肠黏膜屏障功能障碍,依达拉奉对重症急性胰腺炎大鼠肠黏膜屏障功能损害具有保护作用,机制可能与下调氧自由基及细胞因子水平以及下调内皮细胞ICAM-1表达有关。
Objective:The study was designed to investigate the intestinal mucosa barrier function changes in rat with severe acute pancreatitis (SAP),and the intervention effect of edaravone injection and its mechanisms of protection on intestinal mucosa barrier function injury of SAP with the purpose of providing evidence for preventing and curing intestinal mucosa barrier function injury of SAP in clinical practice.
Methods:A total of 60 healthy male Sprauge-Dawley(SD)rats were randomly divided into norm group(Norm),sham-operation group (Sham), SAP group (SAP), edaravone treated group(ED), and each with 18 rats except for norm group(with 6 rats).The latter three groups each had three subgroups at three points:6,12,24 hours.Rats with SAP were prepared with retrograde cholangiopancreatic duct infusion in 5%sodium taurocholate.The dynamic changes of the indexes of intestinal mucosa barrier function injury and pancreas injury were observed at various time points in each group,including the levels of plasma diamine oxidase(DAO) and serum amylase and malondialdehyde (MDA), superoxide dismutase (SOD), intercellular adhesion molecule-1(ICAM-1) in gut. Pathologic changes in pancreas and gut tissues were observed. Statistical analysis was done by SPSS 13.0 statistical software. Frequency distribution of data was examined by the Kolmogorov-Smirnov test.Data according with normal distribution was described with mean±standard deviation (x±s). One-way ANOVA was used to analyse the difference among groups.If the difference was statistically significant, further using SNK method(q test) to compare between groups. The test correlation uses Pearson analysis.
Results:1.Changes of The levels of serum amylase and plasma DAO were not significantly different between Norm group and Sham group.The levels of serum amylase and plasma DAO concentration in SAP group were significantly higher at 6h,12h,24h postoperation than Nrom group and Sham group; The levels of serum amylase and plasma DAO concentration in ED group were lower than SAP group,but higher than Nrom group and Sham group;2.Changes of MDA concentration, SOD activity in intestine were not significantly different between Nrom group and Sham group; Compared with Nrom group and Sham group,The concentration of MDA increased in SAP group at 6h,12h,24h postoperation,but the activity of SOD significantly decreased. The concentration of MDA lower in ED group in all times than SAP group,but higher than Nrom group and Sham group; The activity of SOD was higher in ED group in all times than SAP group,but lower than Nrom group and Sham group.3.Changes of ICAM-1 concentration in intestine were not significantly different between Nrom group and Sham group (P>0.05);Compared with Nrom group and Sham group,The concentration of ICAM-1 significantly increased in SAP group at 6h,12h,24h postoperation; The concentration of ICAM-1 lower in ED group in all times than SAP group,but higher than Nrom group and Sham group.4. Pathologic changes of intestinal tissue in SAP rats included villusand lamina loss,exposed,submucosal vascular congestion and so on. Pathologic changes of pancreatic tissue in SAP rats included edema, bleeding,necrosis and inflammatory cells infiltration.No pathologic damage of pancreatic tissue and intestinal tissue were seen in Nrom group and Sham group;The pathologic damage of pancreatic tissue was alleviated evidently in ED group comparied with SAP group; No pathologic damage of intestinal tissue was seen in SAP group and ED group.5.There was positive correlation between the concentration of plasma DAO and MDA,but negtive correlation between the concentration of plasma DAO and the activity of SOD; There was positive correlation between the concentration of plasma DAO and ICAM-1.
Conclusion:The function of intestinal mucosal barrier is damaged in the early phases of SAP.Edaravone can protect the damages of intestinal mucosa barrier function in SAP rats,probably through reducing free radicals,cytokines and the ICAM-1 expressing the endothelia cells.
方法：60只清洁级SD大鼠随机分为正常组(Norm组)(n=6)、假手术组(Sham组)(n=18)、重症急性胰腺炎组(SAP组)(n=18)和依达拉奉治疗组(ED组)(n=18)。Norm组不做任何处理；Sham组在开腹后仅翻动胰腺后关腹；SAP组采用逆行十二指肠胰胆管注射5%牛黄胆酸钠溶液制备SAP大鼠模型；ED组模型制备成功后即刻经尾静脉注射3mg/kg的依达拉奉。分别在建模成功后6h、12h、24h采集血液、肠道、胰腺标本。检测各组不同时间点血浆二胺氧化酶(DAO),血淀粉酶,及肠道组织中的丙二醛(MDA),超氧化物歧化酶(SOD),细胞间黏附分子-1(ICAM-1)水平,并且光镜观察肠道及胰腺病理形态的改变。采用SPSS13.0统计软件。Kolmogorow-Smirnow法对各组数据进行正态性检验,符合正态分布则用均数±标准差(x±s)描述,用单因素方差分析(one-way ANOVA分析)行组间差异比较,若各组间差异有统计学意义,进一步用SNK法(q检验)进行两两间比较,采用Pearson相关分析方法进行相关分析。
结果：1.Norm组与Sham组血浆DAO水平差别无统计学意义(P>0.05)；SAP组大鼠术后6h,12h,24h血浆DAO浓度和血淀粉酶浓度均高于Norm组和Sham组(P<0.05)；ED组血浆DAO浓度和血淀粉酶浓度较Norm组和Sham组升高(P<0.05),但较SAP组降低(P<0.05)。2.Norm组与Sham组肠道组织MDA,SOD水平差别无统计学意义(P>0.05)；与Norm组及Sham组相比,SAP组MDA水平3个时间点依次升高(P<0.05)；SOD活性3个时间点依次下降(P<0.05)；ED组较SAP组MDA水平均明显降低,SOD活性明显升高(P<0.05)。3.Nrom组与Sham组肠道组织ICAM-1水平差别无统计学意义(P>0.05)；与Nrom组及Sham组相比,SAP组肠道ICAM-1水平在3个时间点均明显升高(P<0.05)；ED组肠道ICAM-1水平较SAP组下降(P<0.05),但仍高于Nrom组和Sham组(P<0.05)。4.SAP组肠道组织病理学改变包括绒毛,固有层脱落,裸露,黏膜下毛细血管充血；胰腺组织病理学改变包括严重的水肿,出血,坏死,炎症细胞浸润;Norm组和Sham组胰腺及肠道评分差别无统计学意义(P>0.05)；SAP组肠道和胰腺组织损伤病理评分明显高于Nrom组和Sham组(P<0.05)；ED组肠道组织损伤病理评分较SAP组无统计学意义(P>0.05),但仍高于Nrom组和Sham组(P<0.05)；ED组胰腺组织损伤病理评分较SAP组低(P<0.05),但仍高于Nrom组和Sham组(P<0.05)。5.血浆DAO水平与肠道MDA水平呈明显正相关(P<0.01),与肠道SOD活性呈明显负相关(P<0.01)；血浆DAO与肠道组织ICAM-1水平呈明显正相关(P<0.01)。
结论：SAP早期即存在肠黏膜屏障功能障碍,依达拉奉对重症急性胰腺炎大鼠肠黏膜屏障功能损害具有保护作用,机制可能与下调氧自由基及细胞因子水平以及下调内皮细胞ICAM-1表达有关。
Objective:The study was designed to investigate the intestinal mucosa barrier function changes in rat with severe acute pancreatitis (SAP),and the intervention effect of edaravone injection and its mechanisms of protection on intestinal mucosa barrier function injury of SAP with the purpose of providing evidence for preventing and curing intestinal mucosa barrier function injury of SAP in clinical practice.
Methods:A total of 60 healthy male Sprauge-Dawley(SD)rats were randomly divided into norm group(Norm),sham-operation group (Sham), SAP group (SAP), edaravone treated group(ED), and each with 18 rats except for norm group(with 6 rats).The latter three groups each had three subgroups at three points:6,12,24 hours.Rats with SAP were prepared with retrograde cholangiopancreatic duct infusion in 5%sodium taurocholate.The dynamic changes of the indexes of intestinal mucosa barrier function injury and pancreas injury were observed at various time points in each group,including the levels of plasma diamine oxidase(DAO) and serum amylase and malondialdehyde (MDA), superoxide dismutase (SOD), intercellular adhesion molecule-1(ICAM-1) in gut. Pathologic changes in pancreas and gut tissues were observed. Statistical analysis was done by SPSS 13.0 statistical software. Frequency distribution of data was examined by the Kolmogorov-Smirnov test.Data according with normal distribution was described with mean±standard deviation (x±s). One-way ANOVA was used to analyse the difference among groups.If the difference was statistically significant, further using SNK method(q test) to compare between groups. The test correlation uses Pearson analysis.
Results:1.Changes of The levels of serum amylase and plasma DAO were not significantly different between Norm group and Sham group.The levels of serum amylase and plasma DAO concentration in SAP group were significantly higher at 6h,12h,24h postoperation than Nrom group and Sham group; The levels of serum amylase and plasma DAO concentration in ED group were lower than SAP group,but higher than Nrom group and Sham group;2.Changes of MDA concentration, SOD activity in intestine were not significantly different between Nrom group and Sham group; Compared with Nrom group and Sham group,The concentration of MDA increased in SAP group at 6h,12h,24h postoperation,but the activity of SOD significantly decreased. The concentration of MDA lower in ED group in all times than SAP group,but higher than Nrom group and Sham group; The activity of SOD was higher in ED group in all times than SAP group,but lower than Nrom group and Sham group.3.Changes of ICAM-1 concentration in intestine were not significantly different between Nrom group and Sham group (P>0.05);Compared with Nrom group and Sham group,The concentration of ICAM-1 significantly increased in SAP group at 6h,12h,24h postoperation; The concentration of ICAM-1 lower in ED group in all times than SAP group,but higher than Nrom group and Sham group.4. Pathologic changes of intestinal tissue in SAP rats included villusand lamina loss,exposed,submucosal vascular congestion and so on. Pathologic changes of pancreatic tissue in SAP rats included edema, bleeding,necrosis and inflammatory cells infiltration.No pathologic damage of pancreatic tissue and intestinal tissue were seen in Nrom group and Sham group;The pathologic damage of pancreatic tissue was alleviated evidently in ED group comparied with SAP group; No pathologic damage of intestinal tissue was seen in SAP group and ED group.5.There was positive correlation between the concentration of plasma DAO and MDA,but negtive correlation between the concentration of plasma DAO and the activity of SOD; There was positive correlation between the concentration of plasma DAO and ICAM-1.
Conclusion:The function of intestinal mucosal barrier is damaged in the early phases of SAP.Edaravone can protect the damages of intestinal mucosa barrier function in SAP rats,probably through reducing free radicals,cytokines and the ICAM-1 expressing the endothelia cells.
引文
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[23]王丽杰,孙梅.血小板活化因子受体拮抗剂对内毒素血症幼年大鼠肠粘膜上皮细胞间连接蛋白的影响[J].中国危重病急救医学,2007,19(8)：96-99
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[27]草海军,陈李华.肠屏障功能障碍的研究现状与展望[J].国际消化病杂志,2007,27(6)：436-437
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[29]蒋晓云,钱立平.重症急性胰腺炎肠道屏障功能损伤机制研究进展[J].国际消化病杂志,2006,26(4)：221-223
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[39]房林,薛崇德等.精氨酸对肠粘膜屏障功能的影响[J].华夏医学,2000,13(2)：124-126
[40]蒋小华,李宁等.精氨酸对短肠综合征大鼠肠道代偿的影响[J].中华实验外科杂志,2007,24(8)：1024
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[46]孙晓庆.创伤后肠道通透性改变血浆标志物D-乳酸的实验研究[J].中国危重病急救医学,2000,12(8)：476-478
[47]刘晓昌,梅俏等。肠黏膜屏障功能监测研究进展[J].山东医药,2009,49(17)：106-107
[48]赵海东,田晓峰等.肠型脂肪酸结合蛋白对肠缺血早期诊断的意义[J].中国普通外科杂志,2004,13(7)：513-516
[49]肠黏膜屏障功能评价指标的检测和应用[J].医学综述,2010,16(4)：623-625
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