伴高脂血症性急性坏死性胰腺炎大鼠的肠道免疫功能及肠粘膜谷氨酰胺代谢改变的实验研究
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摘要
目的:建立高脂血症(HL)及急性坏死性胰腺炎(ANP)大鼠模型;观察伴或不伴HL状态的ANP大鼠的肠道免疫功能改变以及肠黏膜谷氨酰胺(Gln)代谢的改变,探讨肠黏膜Gln代谢的改变与伴高脂血症急性坏死性胰腺炎(HL+ANP)大鼠及ANP大鼠肠道免疫功能下降的关系,以期进一步了解ANP时肠道免疫功能损伤可能的机制及高脂血症加重ANP关于肠道免疫功能方面的机制。
方法:40只雄性SD大鼠,随机等分为4组:正常对照组,HL组,ANP组, HL+ANP组。具体方法:首先随机分为2组(N=20),分别用基础饲料和高脂饲料(主要成分为87.8%基础饲料+10%猪油+2%胆固醇+0.2%胆酸钠)喂养4周建立大鼠高脂血症模型,4周后两组内再随机分为两组(n=10),采用逆行胰胆管注射3.5%牛磺胆酸钠制作大鼠ANP模型,另外一对照组逆行胰胆管注射生理盐水。建立ANP模型24小时后处死动物,取材并观察胰腺组织病理改变;检测血清淀粉酶(AMS)、甘油三脂(TG)水平,鲎试剂法检测门静脉血内毒素水平,免疫组化方法检测小肠黏膜组织CD4+、CD8+ T淋巴细胞数量,免疫放射分析法测定肠黏膜组织中分泌型免疫球蛋白A(sIgA)含量,分光光度计法方法测定肠道Gln摄取率、肠黏膜Gln含量、谷氨酰胺酶(GA)活力。
结果: HL组血清TG值较对照组明显升高(P﹤0.01),ANP组较对照组血AMS明显升高(P﹤0.01),胰腺组织出现出血及坏死等病理改变,血内毒素水平显著增高(P﹤0.01),小肠黏膜组织CD4+、CD8+ T淋巴细胞数量、sIgA含量、肠道Gln摄取率、肠黏膜Gln含量、GA活力较对照组显著降低(P﹤0.01～P﹤0.05);HL+ANP组较ANP组胰腺坏死更为明显(P﹤0.05),血清TG值明显升高(P﹤0.01),血内毒素水平显著增高(P﹤0.01),小肠黏膜组织CD4+、CD8+ T淋巴细胞数量、sIgA含量、肠道Gln摄取率、肠黏膜Gln含量、GA活力显著降低(P﹤0.01～P﹤0.05)。
结论:高脂食料喂养4周可建立高脂血症动物模型,结合逆行胰胆管注射3.5%牛磺胆酸钠溶液可成功建立伴高脂血症大鼠ANP模型;ANP早期即出现肠道免疫功能受损,肠黏膜Gln代谢改变可能在这一损伤过程中起重要作用;高脂血症可加重ANP大鼠肠道免疫功能受损,而肠黏膜Gln代谢改变可能是高脂血症加重ANP肠道免疫功能受损的机制之一。
Objective: To build a model of rats suffered from hyperlipemia (HL)and acute necrotic pancreatitis(ANP). To observe the change of intestinal immune function and glutamine metabolism in the intestinal mucosa in ANP in rats with and without HL,and to explore the relationship between the change of intestinal immune function and glutamine metabolism in the intestinal mucosa in rats with HL and ANP to learn further the possible mechanism of the injury of intestinal immune function in ANP and the mechanism on intestinal immune function that HL aggravate the pathogenetic condition in ANP.
Methods: 40 male SD rats were randomly divided into 4 groups: control group, HL group,ANP group,HL+ANP group.The specific methods are as follows :First,the rats were randomly divided into two groups(N=20) , respectively feeding normal diet and high-fat diet (which consist of 87.8%nomal diet , 10% lard ,2% cholesterol and 0.2%sodium cholate) for 4 weeks.After 4 weeks,each group was randomly devided into two groups(n=10) again and used retrograde injection 3.5% sodium taurocholate which induced severe acute pancreatitis and NS into the pancreatic duct respectively. Rats were sacrificed ,and the materials were gained at 24 hours after models were made. To observed the histopathologic damage degree of pancreas and measure the value of amylase (AMS)、triglyceride (TG) in serum. Endotoxin concentration in portal vein was determined by limulus methods;CD4+, CD8+T lymphocytes in intestinal mucosa were examined by immunohistochemistry;the sIgA contents of intestinal mucosa was examined by radioimmunoassay;the glutamine uptake rate、concentration of glutamine and activity of GA in intestinal mucosa was examined by using spectrophotometry.
Results: The serum TG value in the HL group was higher than that in the control group ( P < 0. 01) . .Compared to the control group ,the pancreas were found to get bleeding and necrosis histopathologic change,and the level of AMS in serum and plasma endotoxin concentration in the portal vein increased, and the levels of CD4+、CD8+T lymphocyte ,sIgA ,glutamine uptake rate,glutamine and activity of GA in the intestinal mucosa reduced significantly in the ANP group (P<0.01～P<0.05);Compared to the ANP group ,the HL+ANP group had more serious histopathologic change , higher levels of AMS and TG in serum and plasma endotoxin concentration in the portal vein ,and lower levels of CD4+、CD8+T lymphocyte , sIgA , glutamine uptake rate , glutamine and activity of GA in the intestinal mucosa(P<0.01～P<0.05).
Conclusion: An ideal animal model.of HL can be builded by feeding high-fat diet for 4 weeks.A model of ANP complicated with hyperlipemia in rat might be developed by feeding high-fat diet for 4 weeks and retrograde injection of 3.5% sodium taurocholate into the pancreatic duct.Intestinal immune suppression occurred in the early stage of ANP,and the change of glutamine metabolism in the intestinal mucosa may play an important role here. HL can make ANP more serious through intestinal immune suppression way,and the change of glutamine metabolism in the intestinal mucosa may play an important role here.
方法:40只雄性SD大鼠,随机等分为4组:正常对照组,HL组,ANP组, HL+ANP组。具体方法:首先随机分为2组(N=20),分别用基础饲料和高脂饲料(主要成分为87.8%基础饲料+10%猪油+2%胆固醇+0.2%胆酸钠)喂养4周建立大鼠高脂血症模型,4周后两组内再随机分为两组(n=10),采用逆行胰胆管注射3.5%牛磺胆酸钠制作大鼠ANP模型,另外一对照组逆行胰胆管注射生理盐水。建立ANP模型24小时后处死动物,取材并观察胰腺组织病理改变;检测血清淀粉酶(AMS)、甘油三脂(TG)水平,鲎试剂法检测门静脉血内毒素水平,免疫组化方法检测小肠黏膜组织CD4+、CD8+ T淋巴细胞数量,免疫放射分析法测定肠黏膜组织中分泌型免疫球蛋白A(sIgA)含量,分光光度计法方法测定肠道Gln摄取率、肠黏膜Gln含量、谷氨酰胺酶(GA)活力。
结果: HL组血清TG值较对照组明显升高(P﹤0.01),ANP组较对照组血AMS明显升高(P﹤0.01),胰腺组织出现出血及坏死等病理改变,血内毒素水平显著增高(P﹤0.01),小肠黏膜组织CD4+、CD8+ T淋巴细胞数量、sIgA含量、肠道Gln摄取率、肠黏膜Gln含量、GA活力较对照组显著降低(P﹤0.01～P﹤0.05);HL+ANP组较ANP组胰腺坏死更为明显(P﹤0.05),血清TG值明显升高(P﹤0.01),血内毒素水平显著增高(P﹤0.01),小肠黏膜组织CD4+、CD8+ T淋巴细胞数量、sIgA含量、肠道Gln摄取率、肠黏膜Gln含量、GA活力显著降低(P﹤0.01～P﹤0.05)。
结论:高脂食料喂养4周可建立高脂血症动物模型,结合逆行胰胆管注射3.5%牛磺胆酸钠溶液可成功建立伴高脂血症大鼠ANP模型;ANP早期即出现肠道免疫功能受损,肠黏膜Gln代谢改变可能在这一损伤过程中起重要作用;高脂血症可加重ANP大鼠肠道免疫功能受损,而肠黏膜Gln代谢改变可能是高脂血症加重ANP肠道免疫功能受损的机制之一。
Objective: To build a model of rats suffered from hyperlipemia (HL)and acute necrotic pancreatitis(ANP). To observe the change of intestinal immune function and glutamine metabolism in the intestinal mucosa in ANP in rats with and without HL,and to explore the relationship between the change of intestinal immune function and glutamine metabolism in the intestinal mucosa in rats with HL and ANP to learn further the possible mechanism of the injury of intestinal immune function in ANP and the mechanism on intestinal immune function that HL aggravate the pathogenetic condition in ANP.
Methods: 40 male SD rats were randomly divided into 4 groups: control group, HL group,ANP group,HL+ANP group.The specific methods are as follows :First,the rats were randomly divided into two groups(N=20) , respectively feeding normal diet and high-fat diet (which consist of 87.8%nomal diet , 10% lard ,2% cholesterol and 0.2%sodium cholate) for 4 weeks.After 4 weeks,each group was randomly devided into two groups(n=10) again and used retrograde injection 3.5% sodium taurocholate which induced severe acute pancreatitis and NS into the pancreatic duct respectively. Rats were sacrificed ,and the materials were gained at 24 hours after models were made. To observed the histopathologic damage degree of pancreas and measure the value of amylase (AMS)、triglyceride (TG) in serum. Endotoxin concentration in portal vein was determined by limulus methods;CD4+, CD8+T lymphocytes in intestinal mucosa were examined by immunohistochemistry;the sIgA contents of intestinal mucosa was examined by radioimmunoassay;the glutamine uptake rate、concentration of glutamine and activity of GA in intestinal mucosa was examined by using spectrophotometry.
Results: The serum TG value in the HL group was higher than that in the control group ( P < 0. 01) . .Compared to the control group ,the pancreas were found to get bleeding and necrosis histopathologic change,and the level of AMS in serum and plasma endotoxin concentration in the portal vein increased, and the levels of CD4+、CD8+T lymphocyte ,sIgA ,glutamine uptake rate,glutamine and activity of GA in the intestinal mucosa reduced significantly in the ANP group (P<0.01～P<0.05);Compared to the ANP group ,the HL+ANP group had more serious histopathologic change , higher levels of AMS and TG in serum and plasma endotoxin concentration in the portal vein ,and lower levels of CD4+、CD8+T lymphocyte , sIgA , glutamine uptake rate , glutamine and activity of GA in the intestinal mucosa(P<0.01～P<0.05).
Conclusion: An ideal animal model.of HL can be builded by feeding high-fat diet for 4 weeks.A model of ANP complicated with hyperlipemia in rat might be developed by feeding high-fat diet for 4 weeks and retrograde injection of 3.5% sodium taurocholate into the pancreatic duct.Intestinal immune suppression occurred in the early stage of ANP,and the change of glutamine metabolism in the intestinal mucosa may play an important role here. HL can make ANP more serious through intestinal immune suppression way,and the change of glutamine metabolism in the intestinal mucosa may play an important role here.
引文
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2. Foitzik TF, Femandez-del Castillo C, Ferraro MJ, Mithofer K, Rattner DW, Warshaw AL. Pathogenesis and prevention of early pancreatic infection in experimental acute necrotizing pancreatitis. [J]. Ann Surg, 1995;222:179-185
3. Kazantsev GB, Hecht DW, Rao R, Fedorak IJ, Gattuso P, Thompson K, Djuricin G, Prinz RA. Plasmid labeling confirms bacterial translocation in pancreatitis. [J]. Am J Surg, 1994;167:201-207
4. Mole DJ, Taylor MA, McFerran NV, Diamond T. The isolated perfused liver response to a‘second hit’of portal endotoxin during severe acute pancreatitis. [J]. Pancreatology,2005; 5: 475-485
5. Closa D, Folch-Puy E.Oxygen free radicals and the systemic inflamm- atory response. [J].IUBMB Life,2004;56: 185-191
6.李晓芳.严重烧伤后胃肠道功能障碍的机制和防治[J].世界华人消化杂志,2006,14(9):888-893
7.彭乃宝.维护肠道屏障功能的重要性及措施[J].齐齐哈尔医学院学报,2005 ,26(10):1182-1184.
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