甘草甜素对重症急性胰腺炎大鼠NF-κB、TNF-α、IL-1β、IL-6、ICAM-1的影响
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摘要
目的通过研究重症急性胰腺炎大鼠应用甘草甜素后其肿瘤坏死因子-α、白介素-1β、白介素- 6、核转录因子-κB、肠粘膜ICAM-1的动态变化,探讨甘草甜素对急性重症胰腺炎治疗的可能作用机制。
方法150只健康雄性Sprague-Dawley大鼠,体重160-200g,随机(随机表法)分为假手术组(S组)、重症急性胰腺炎(P组)和重症急性胰腺炎甘草甜素治疗组(GL组),每组50只。每组10只,检测72h内的生存时间,P组和GL组采用戊巴比妥钠腹腔注射麻醉下逆行胰胆管穿刺泵推5%牛磺胆酸钠建立SAP模型。GL组大鼠在术后腹腔内注射甘草甜素(100mg/kg)。分别于术后3h、6h、12h、24h四个时间点采用腹主动脉放血法将大鼠分批处死(每组10只),全自动生化分析仪检测血淀粉酶,采用放射免疫法测血清炎症细胞因子TNF-α、IL-1β、IL-6的水平;取胰腺组织免疫组化检测胰腺组织NF-κBp65活性,同时进行胰腺组织病理学评分的测定,取回肠组织免疫组化检测回肠黏膜ICAM-1的表达,同时进行回肠黏膜组织病理学评分的测定,并观察甘草甜素预处理后上述各指标的变化。应用SPSS16.0版统计软件进行分析,主要统计指标进行正态性检验和方差齐性检验,各统计数据均以( X±s)表示;多组均数间的比较采用one-wayANOVA检验,多组均数间的两两比较采用DunnettT3法, P<0.05为差异显著有统计学意义。
结果(1)大鼠生存时间GL组与P组相比,GL组的生存时间明显延长,P=0.021(P<0.05)差异具有统计学意义。血清血淀粉、TNF-α、IL-1β、IL-6含量变化:与S组相比,P组、GL组各时间点均明显升高(P<0.005),P组与GL组相比,GL组低于同时间点P组,但TNF-α、IL-1β在3h差异无统计学意义,分别为P=0.280、P=0.350 (P>0.05),血淀粉、IL-6在3h差异有统计学意义,分别为P=0.023、P=0.024 (P<0.05)但在6h、12h、18h均有显著性差异.其中6h分别:P=0.019、P=0.012、P=0.022、P=0.018 (P<0.05).12h分别为:P=0.027、P=0.024、P=0.015、P=0.013 (P<0.05),24h分别为:P=0.027、P=0.025、P=0.032、P=0.015 (P<0.05)。
(2)胰腺组织、肠粘膜病理学评分:与S组相比,P组、GL组各时间点均明显升高,差异有统计学意义(P<0.05),与P组相比,GL组低于同时间点P组,在3h差异无统计学意义,分别为P=0.261、P=0.378(P>0.05)但在6h、12h、18h有显著性差异,胰腺组织病理比较,分别为6h:P=0.025、12h:P=0.021、24h:P=0.019(P<0.05)肠粘膜组织病理比较,分别为6h:P=0.032、12h:P=0.022、24h:P=0.017(P<0.05)。
(3)胰腺组织NF-κBp65,肠粘膜组织ICAM-1活性的变化:与S组相比,P组、GL组各时间点均明显升高,差异有统计学意义(P<0.05).胰腺组织NF-κBp65:P组与GL组相比,在24h差异无统计学意义P=0.280(P>0.05),但在3h、6h、12h差异有显著性,分别为:3h:P=0.016、6h:P=0.022、12h:P=0.025(P<0.05)。肠粘膜组织ICAM-1:P组与GL组相比,在3h差异无统计学意义,P=0.248(P>0.05)但在6h、12h、24h差异有显著性,分别为:6h:P=0.025、12h:P=0.018、24h:P=0.022(P<0.05)。
结论1.甘草甜素可降低SAP大鼠血清中TNF-α、IL-1β、IL-6浓度,抑制胰腺组织中NF-κBp65、肠粘膜组织ICAM-1的活性,具有抑制炎症作用。
2.甘草甜素具有糖皮质激素样作用,可以减轻重症胰腺炎炎症反应,这可能为今后治疗SAP提供了一条新途径。
Objectives To research the changes of the tumor necrosis factor-α, IL-1β, interleukin-6, nuclear factor-κB, ICAM-1 of the mucosa after the application of glycyrrhizin in rats with severe acute pancreatitis, To study the possible effect mechanism of glycyrrhizin on severe acute pancreatitis
Methods 150 healthy male Sprague-Dawley rats weighing 160-200g, which were randomly divided into sham operationgroup( S group) , severe acute pancreatitis group(P group) and the treatment group with glycyrrhizin of the severe acute pancreatitis (GL group),each group are 50. , the ten detect the survival time of the 72h with each group, P group and GL group are established the SAP model by Puncturing retrograde cholangiopancreatography and pumping 5% sodium taurocholate with intraperitoneal injecting anesthesia through abdominal of the Sodium pento-barbital.Rats in GL group were injected glycyrrhizin after surgery(100mg/kg) ,and at 3h, 6h, 12h, 24h four time points rats were sacrificed in groups using abdominal aortic phlebotomy (n = 10), serum amylas measured by automatic biochemical analyzer ,serum inflammatory cytokines IL-1β, IL-6, TNF-αlevels measured by radioimmunoassay, the activity of NF-κBp65 in pancreatic were detected by immunohistochemistry , at the same time, the scores of pancreatic tissue pathology were detected,the expression of ICAM-1 in ileal mucosa adhesion were detected by immunohistochemistry , at the same time the scores of ileal mucosa pathology were detected and observed the changes of the above indicators after glycyrrhizin pretreatment .All Statistical analysis were performed with SPSS16.0.Main Statistical indicators should be taken normality and homogeneity test,each data were expressed with Mean±standard deviation value,and Several more groups were compared by one-way ANOVA,two groups were analysed by DunnettT3 ,.If the P is less than 0.05 ,It is considered statistical significance. Results
Results (1) the survival time of GL groupRats compared with the P group, the survival time of GL group were significantly prolonged , P = 0.021 (P<0.05), difference was statistically significant. The content change of the blood serum amylase, TNF-α、IL-1βand IL-6 is: Compared with S group , the P group and GL group were significantly increased at each time point, P group compared with the GL, GL group was lower than SAP group at the same time point,but TNF-α、IL-1βshowed no significant difference in 3 h point, they respectively are :P = 0.280、P = 0.350 (P>0.05), serum amylase、IL-6 showed significantly difference in 3h point , they respectively are :P = 0.023、P = 0.024(P<0.05),but they are significantly different in 6h, 12h, 18h point . In the 6h point they respectively are: P = 0.019、P = 0.012、P = 0.022、P = 0.018 (P<0.05) .In the 6h point they respectively are: P = 0.027、P = 0.024、P = 0.015.、P = 0.013 (P<0.05) In the 6h point they respectively are : P = 0.027.、P = 0.025、P = 0.032、P = 0.015 (P<0.05)
(2) the pathological scores of pancreas and intestinal mucosa: P group and GL group were significantly higher than S group at each time point, they are significantly different (P<0.05), Compared with the P group, GL group was lower than P group at the same time point ,It showed no significant difference in 3 h point, they respectively are : P = 0.261、P = 0.378 (P>0.05) but they are significantly different in 6h, 12h, 18h point, the comparison of pancreatic pathology :they respectively are:6h: P = 0.025、12h: P = 0.021、24h: P = 0.019 (P<0.05) .the comparison of intestinal pathology :they respectively are 6h : P = 0.032、12h: P = 0.022、24h: P = 0.017 (P<0.05).
(3) the activity change of NF-κB p65 in pancreatic and ICAM-1 in intestinal mucosa: P group and GL group were significantly higher than S group at each time point, they are significantly different (P<0.05), the activity change of NF-κB p65 in pancreatic,GL group was lower than P group at the same time point ,It showed no significant difference in 24h point P = 0.280 (P>0.05), but they are significantly different in 3h、6h、12h point, they respectively are:3h: P = 0.016、6h: P = 0.022、12h: P = 0.025 (P<0.05) .the activity change of ICAM-1 in intestinal mucosa ,GL group was lower than P group at the same time point ,It showed no significant difference in 3h point P = 0.248 (P>0.05), but they are significantly different in 6h、12h、24h point, they respectively are:6h: P = 0.025、12h: P = 0.018、24h: P = 0.022 (P<0.05) .
Conclusions 1. Glycyrrhizin may reduce the concentration of TNF-α, IL-1β, IL-6 in the serum of the Severe acute pancreatitis and have inhibit inflammation.
2.Glycyrrhizin with glucocorticoid-like effects, may reduce inflammation in severe acute pancreatitis, which may treat SAP to provide a new way in the future
方法150只健康雄性Sprague-Dawley大鼠,体重160-200g,随机(随机表法)分为假手术组(S组)、重症急性胰腺炎(P组)和重症急性胰腺炎甘草甜素治疗组(GL组),每组50只。每组10只,检测72h内的生存时间,P组和GL组采用戊巴比妥钠腹腔注射麻醉下逆行胰胆管穿刺泵推5%牛磺胆酸钠建立SAP模型。GL组大鼠在术后腹腔内注射甘草甜素(100mg/kg)。分别于术后3h、6h、12h、24h四个时间点采用腹主动脉放血法将大鼠分批处死(每组10只),全自动生化分析仪检测血淀粉酶,采用放射免疫法测血清炎症细胞因子TNF-α、IL-1β、IL-6的水平;取胰腺组织免疫组化检测胰腺组织NF-κBp65活性,同时进行胰腺组织病理学评分的测定,取回肠组织免疫组化检测回肠黏膜ICAM-1的表达,同时进行回肠黏膜组织病理学评分的测定,并观察甘草甜素预处理后上述各指标的变化。应用SPSS16.0版统计软件进行分析,主要统计指标进行正态性检验和方差齐性检验,各统计数据均以( X±s)表示;多组均数间的比较采用one-wayANOVA检验,多组均数间的两两比较采用DunnettT3法, P<0.05为差异显著有统计学意义。
结果(1)大鼠生存时间GL组与P组相比,GL组的生存时间明显延长,P=0.021(P<0.05)差异具有统计学意义。血清血淀粉、TNF-α、IL-1β、IL-6含量变化:与S组相比,P组、GL组各时间点均明显升高(P<0.005),P组与GL组相比,GL组低于同时间点P组,但TNF-α、IL-1β在3h差异无统计学意义,分别为P=0.280、P=0.350 (P>0.05),血淀粉、IL-6在3h差异有统计学意义,分别为P=0.023、P=0.024 (P<0.05)但在6h、12h、18h均有显著性差异.其中6h分别:P=0.019、P=0.012、P=0.022、P=0.018 (P<0.05).12h分别为:P=0.027、P=0.024、P=0.015、P=0.013 (P<0.05),24h分别为:P=0.027、P=0.025、P=0.032、P=0.015 (P<0.05)。
(2)胰腺组织、肠粘膜病理学评分:与S组相比,P组、GL组各时间点均明显升高,差异有统计学意义(P<0.05),与P组相比,GL组低于同时间点P组,在3h差异无统计学意义,分别为P=0.261、P=0.378(P>0.05)但在6h、12h、18h有显著性差异,胰腺组织病理比较,分别为6h:P=0.025、12h:P=0.021、24h:P=0.019(P<0.05)肠粘膜组织病理比较,分别为6h:P=0.032、12h:P=0.022、24h:P=0.017(P<0.05)。
(3)胰腺组织NF-κBp65,肠粘膜组织ICAM-1活性的变化:与S组相比,P组、GL组各时间点均明显升高,差异有统计学意义(P<0.05).胰腺组织NF-κBp65:P组与GL组相比,在24h差异无统计学意义P=0.280(P>0.05),但在3h、6h、12h差异有显著性,分别为:3h:P=0.016、6h:P=0.022、12h:P=0.025(P<0.05)。肠粘膜组织ICAM-1:P组与GL组相比,在3h差异无统计学意义,P=0.248(P>0.05)但在6h、12h、24h差异有显著性,分别为:6h:P=0.025、12h:P=0.018、24h:P=0.022(P<0.05)。
结论1.甘草甜素可降低SAP大鼠血清中TNF-α、IL-1β、IL-6浓度,抑制胰腺组织中NF-κBp65、肠粘膜组织ICAM-1的活性,具有抑制炎症作用。
2.甘草甜素具有糖皮质激素样作用,可以减轻重症胰腺炎炎症反应,这可能为今后治疗SAP提供了一条新途径。
Objectives To research the changes of the tumor necrosis factor-α, IL-1β, interleukin-6, nuclear factor-κB, ICAM-1 of the mucosa after the application of glycyrrhizin in rats with severe acute pancreatitis, To study the possible effect mechanism of glycyrrhizin on severe acute pancreatitis
Methods 150 healthy male Sprague-Dawley rats weighing 160-200g, which were randomly divided into sham operationgroup( S group) , severe acute pancreatitis group(P group) and the treatment group with glycyrrhizin of the severe acute pancreatitis (GL group),each group are 50. , the ten detect the survival time of the 72h with each group, P group and GL group are established the SAP model by Puncturing retrograde cholangiopancreatography and pumping 5% sodium taurocholate with intraperitoneal injecting anesthesia through abdominal of the Sodium pento-barbital.Rats in GL group were injected glycyrrhizin after surgery(100mg/kg) ,and at 3h, 6h, 12h, 24h four time points rats were sacrificed in groups using abdominal aortic phlebotomy (n = 10), serum amylas measured by automatic biochemical analyzer ,serum inflammatory cytokines IL-1β, IL-6, TNF-αlevels measured by radioimmunoassay, the activity of NF-κBp65 in pancreatic were detected by immunohistochemistry , at the same time, the scores of pancreatic tissue pathology were detected,the expression of ICAM-1 in ileal mucosa adhesion were detected by immunohistochemistry , at the same time the scores of ileal mucosa pathology were detected and observed the changes of the above indicators after glycyrrhizin pretreatment .All Statistical analysis were performed with SPSS16.0.Main Statistical indicators should be taken normality and homogeneity test,each data were expressed with Mean±standard deviation value,and Several more groups were compared by one-way ANOVA,two groups were analysed by DunnettT3 ,.If the P is less than 0.05 ,It is considered statistical significance. Results
Results (1) the survival time of GL groupRats compared with the P group, the survival time of GL group were significantly prolonged , P = 0.021 (P<0.05), difference was statistically significant. The content change of the blood serum amylase, TNF-α、IL-1βand IL-6 is: Compared with S group , the P group and GL group were significantly increased at each time point, P group compared with the GL, GL group was lower than SAP group at the same time point,but TNF-α、IL-1βshowed no significant difference in 3 h point, they respectively are :P = 0.280、P = 0.350 (P>0.05), serum amylase、IL-6 showed significantly difference in 3h point , they respectively are :P = 0.023、P = 0.024(P<0.05),but they are significantly different in 6h, 12h, 18h point . In the 6h point they respectively are: P = 0.019、P = 0.012、P = 0.022、P = 0.018 (P<0.05) .In the 6h point they respectively are: P = 0.027、P = 0.024、P = 0.015.、P = 0.013 (P<0.05) In the 6h point they respectively are : P = 0.027.、P = 0.025、P = 0.032、P = 0.015 (P<0.05)
(2) the pathological scores of pancreas and intestinal mucosa: P group and GL group were significantly higher than S group at each time point, they are significantly different (P<0.05), Compared with the P group, GL group was lower than P group at the same time point ,It showed no significant difference in 3 h point, they respectively are : P = 0.261、P = 0.378 (P>0.05) but they are significantly different in 6h, 12h, 18h point, the comparison of pancreatic pathology :they respectively are:6h: P = 0.025、12h: P = 0.021、24h: P = 0.019 (P<0.05) .the comparison of intestinal pathology :they respectively are 6h : P = 0.032、12h: P = 0.022、24h: P = 0.017 (P<0.05).
(3) the activity change of NF-κB p65 in pancreatic and ICAM-1 in intestinal mucosa: P group and GL group were significantly higher than S group at each time point, they are significantly different (P<0.05), the activity change of NF-κB p65 in pancreatic,GL group was lower than P group at the same time point ,It showed no significant difference in 24h point P = 0.280 (P>0.05), but they are significantly different in 3h、6h、12h point, they respectively are:3h: P = 0.016、6h: P = 0.022、12h: P = 0.025 (P<0.05) .the activity change of ICAM-1 in intestinal mucosa ,GL group was lower than P group at the same time point ,It showed no significant difference in 3h point P = 0.248 (P>0.05), but they are significantly different in 6h、12h、24h point, they respectively are:6h: P = 0.025、12h: P = 0.018、24h: P = 0.022 (P<0.05) .
Conclusions 1. Glycyrrhizin may reduce the concentration of TNF-α, IL-1β, IL-6 in the serum of the Severe acute pancreatitis and have inhibit inflammation.
2.Glycyrrhizin with glucocorticoid-like effects, may reduce inflammation in severe acute pancreatitis, which may treat SAP to provide a new way in the future
引文
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[30] Leser HG,Gorss,V,Scheibenbogen C,et al.Elevation of serum interleukin-6 con- Centration Precedes acute-Phase response and reflects severity in acute Panc- reatitis.Gastroenterology,1991,101(3):782-785. .
[31] Stephenson HE,Pfefer RB,saypol GM,et al.Acute hermorrhagic pancrea- titis:report of a case with cortison treamlent[J].Arch Surg,1952,65(3):307.
[32] Miwa Takei, Makiko Kobayashi, David N. Herndon, Richard B. Pollard and ujio Suzuki.Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS) like reactions J Immunol 149 (1998), pp. 1215–1215.
[33] Tsuyoshi Yoshida, Yasuhiro Tsuda, Dan Takeuchi, Makiko Kobayashi, Richar- dB. Pollardand Fujio Suzuki. Glycyrrhizin inhibits neutrophil-associated genera- tion of alternatively activated macrophages Biochem Biophys Res Commun 239 (1995), pp. 577–591.
[34]吕艺,盛志勇,黎君友等.肠缺血-再灌注人鼠小肠血管内皮细胞ICAM-1表达的变化及其与肠损伤的关系.中华普通外科杂志,2000.l5(3):l45-l47.
[35] Kaufmann P,Demel L, Tilz GP. Time course of plasma soluhle intercellular adhesionmole-1 is related to severity of acute pancreatitis.Hepatogastroen- terology.1999.46:2565-2571.
[36] Brider M A, Eppinger M. Gough A, et a1.ICAM-1 expressjon indextran sulfate- induced colitisin rats.Vet Patho1,1997,34(6):598-60.
[1] Hashimoto K,Saito H,et al.The PPAR gamma ligand,15d-PGJattenuates the severity of cerulean-induced actue pancreatitis pancreatitis.Pancreas,2003, Jul,27(1):58-66
[2] Algul H,Tando Y,Schneider G,et al.Actue Experimental pancreatitis and NF- kappaB/Rel Activation[J].Pancreatology,2002,2(2):503-509.
[3] Ethridge RT,Hashimoto K,Chung DH,et al.Selective inhibition of NF-kappa B attenuates the severity of cerulean-induced actue pancreatitis.J Am Coll Surg,2002,195:497-505.
[4] Schmid RM,Adler G NF-kappaB/rel/IkappaB.Implications in gastrointestinal diseases.Gastroenterology,2000,118:1208-1228.
[5] Perkins ND.The Rel/NF-kappa B family:friend and foe[J].Trends Biochem Sci,2000,25(9):434-440.
[6] Denham W Norman J.The potential role of therapeutic cytokine manipulation in actue pancreatitis[J].Cytokine,2002,20(6):295-303.
[7] Mann DA.The NF-kappa B luciferase mouse:a new tool for real time measurement of NF-kappa B activation in the whole enima.Gut,2002, 51:769-770.
[8] Weighardt, H.S.aiserMoore,R.M.Vabulas,C.J.irschning,H.Wagner,B.Holz-mann 2002.Cutting edge:myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection.J.Immunol.169: 2823-2827.
[9] Silverstein,R.2004.D-galactosamine Lethality model:Scopeand Limitations.J. EndotoxinRes.10:147-162.
[10] Qiu J,Hu X,NesiC O,et al.Effect of NF-kappaB oligonucleotidesdes“decoys”on gene expression in P7 rat hippocampus after hypoxia/ischemia[J].J Neuosci Res,2004,77(1):108-118.
[11] Lnae JS,ToddKE,GloorB,et al.Platelet activating factor atagonism,reduce theSy-estmic inflammator rePonse in a murine model of acute Pnacreattiis.J SurgRes,2001,99(2):365-370.
[12] Nomrna JS,FiknGW,SxetonC,ct al.Transgenic animals demonstrate a role for The IL-1 recePtor in regulation IL-1 beta gene exPression at steady-state and during systemic srtess induced by acute Pancreatitis.JSurg Res,1995,63(1) 231-236.
[13] Kusske AM,RongioneAJ,ReberHA,et al.Cytokine and acute ancreatitis.Gas- Rtoenteorlogy,1996,100(2):639一642.
[14] RuaB,Paszkowski A,Esber S,et al.Anti-ICAM-1 antibody modulates late onset Of acinar cell apoptosis and early necrosis in taurocholate-induced experi - mental Acute Pancreatitis.Pancreas,2001,23(l):80-88.
[15] Noman JG,Franz M,RikerA,et al.Rapid elevation of Proinflammatory cytokine during acute Pancreatitis and their origination wihtin the Pancreas.SurgicalFoRum 1994,45:148-156.
[16] HuhgesCB,Henry J,Kotb M,et al.UP-regulation of TNF-αalpha mRNA inthe rat Spleen following induction of Pnacreatitis.J SurgRes,1995,59(6):687-693.
[17] Strieter RM,Kunknel SL,Bone RC.Role of tumor necrosisi factory-alPha in dis- Ease states and inflammation.Crit CARE Med.1993,21(10,suppl):S447-453.
[18] RauB,Paszkowski A,Lillich S,et al.Differential effects of casPase-l/interlekin- 1 bata-converting enzyme on actinar cell necrosis and apoptosis in severe acute Experimental Pancreattiis.Lab Invest,2001,81(7):1001-1013.
[19] GayNJ,Keith FJ.DrosoPhila Toll and IL-l receptor Nature,1991,751,(625)355- 356.
[20] FinkGW,Normna JG.Specific changes in the Pancreatic expression of the in- Terleukin-1 family of genes during experimental acute Pancreariris.Cytokin, 1997,(12):1023-1027.
[21] Norman JG,Fink GW,Denham,w,et al..Tissue-specific cytokine Production dur- Ing experimental acute Pancreattiis.AProbable mechanism for distant organ Dy- sfunction Dig Dis Sei,1997,42(8):1783-1788.
[22] Norman JG,Franz MG,Fink GS,et al.Decreased mortality of severe acute Pan- Creatitis after proXimal cytokine blockade.Ann surg,1995,221(6):625-631.
[23] PaskzowskiAS,Rau,Mayer JM,et al.therapeutic application of casPasel/in- Terleukin-1 bate converting enzyme inhibitor decreased the death rate in severe Acute experimental Pancreatitis.Ann,Sur,2002,235(1):68-76.
[24] Powell JJ,Fearon KC Siriwardena AK,et al.EVidence against a role for Poly- Morphisms at tumor necronsis facftor,interleukin-1 and receptor antagist gene Loci in the regulation of disease severiy in acute Pancreatitis.Surgery,2001,129 (5)633-640.
[25] Bevilacuqe MP,Pober JS,Wheeler ME,et al.IL-1 acts on cultured human vascu Lar endothelium to increase the adhesion of Polymoprhonuclear leuocytes cell line.JClin Invest,1985;2003
[26] tanaka N,Murata A,Uda K,et al.IL-1 recepetor anatgonist modifies changes In vital organs induced by acute necrotic Pancreatitis in an experimental model.Crit Care Med,1995;23:901
[27] Shimada M,Andoh A,Hata K,et al.IL-6 secretion by human pancreatic periaci- nar myofibroblasts in response to inflammatory mediators Immunnol,2002,168 (2):861-6
[28] Geiger,T,Andus,T,Klapproth J,et al.induction of rat acute-phase Protein by in- Terleukin 6 in vivo.Eur J Immunol,1988,(5):717-721.
[29] Leser HG,Gorss,V,Scheibenbogen C,et al.Elevation of serum interleukin-6 con- Centration Precedes acute-Phase response and reflects severity in acute Pancreatitis.Gastroenterology,1991,101(3):782-785.
[30] Inagaki,T,Hoshino M,Haykawa,T,et al.Interleukin-6 is useful marker for Early Prediction of the severity acute Pancreatitis.Panceras,1997,14(l):l-8.
[31] De Beaux AC,Ross JA,Maingy JP,et.al.Proinflammatory cytokine release by PeriPheral blood mononuclear cells form Patient with acute Pancreatitis.BrJ Surg,1996,83(8):1071-1075.
[32] KaW M,Singh S.Serum liPase,C-reactive protein,interleukine-6 levels in ERCP-induced Pancreatitis.Gastroiniest Endosc,2001,54(4):435-440.
[33] Friess H,Shrikhnade S,Riesle E.et al.PhosPholipase A2 isoform in acute pan- creatitis.Ann Surg.2001,233(2):204-212a
[34] AufennagerJ,Samman M,Quintel M,et al.Panceatic PhospholiPase A2 activity In acute Pancreatitis:a Prognostic marker of early identification of patients at ris..Clin Chem Lab Med.2002,40(3):293-297.
[35]杨天德,杨宗城.磷酷酶A2与急性肺损伤.国外医学生理病理科学与临床分册,1997,17(1):24-26.
[36] schrag HJ,Schmitter N,Aufenanger J,et al.Experimental study of a novel phos- Pholipase A2 inhibition in acute Pancreatitis.Br J Surg,1998,85:618-623.
[37] Closa D,Rosello-Catafau J,Martrat A,et al.Changes of systemic Prostacyclin and Thromboxane A2 in sodium taurocholate and cerulean-induced acute Pancreatitis In rats.Dig Dis Sci,1993,38(l):33-38.
[38] Iida T,Yokoi H,Kawarada Y.The effects of a thromboxane A2 synthesis I nhibitor and a Prostaglandin 12 analogue on experimental acute necotizingPancreatitis in rats Pancreas,1998,17(2):140-147
[39] Closa D,et al.Prostanoid and oxygen free radicals in early stages of experimen- tal acute Pancreatitis.Dig Dis Sci,1994,39:1537-1542
[49] Lelcuk S,Alexander,F,Kobzik L,et al.Prostacyclin and TXA2 moderate Postischemic renal failure Surg,1985,98(2):207-212. .
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[30] Leser HG,Gorss,V,Scheibenbogen C,et al.Elevation of serum interleukin-6 con- Centration Precedes acute-Phase response and reflects severity in acute Panc- reatitis.Gastroenterology,1991,101(3):782-785. .
[31] Stephenson HE,Pfefer RB,saypol GM,et al.Acute hermorrhagic pancrea- titis:report of a case with cortison treamlent[J].Arch Surg,1952,65(3):307.
[32] Miwa Takei, Makiko Kobayashi, David N. Herndon, Richard B. Pollard and ujio Suzuki.Glycyrrhizin inhibits the manifestations of anti-inflammatory responses that appear in association with systemic inflammatory response syndrome (SIRS) like reactions J Immunol 149 (1998), pp. 1215–1215.
[33] Tsuyoshi Yoshida, Yasuhiro Tsuda, Dan Takeuchi, Makiko Kobayashi, Richar- dB. Pollardand Fujio Suzuki. Glycyrrhizin inhibits neutrophil-associated genera- tion of alternatively activated macrophages Biochem Biophys Res Commun 239 (1995), pp. 577–591.
[34]吕艺,盛志勇,黎君友等.肠缺血-再灌注人鼠小肠血管内皮细胞ICAM-1表达的变化及其与肠损伤的关系.中华普通外科杂志,2000.l5(3):l45-l47.
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[36] Brider M A, Eppinger M. Gough A, et a1.ICAM-1 expressjon indextran sulfate- induced colitisin rats.Vet Patho1,1997,34(6):598-60.
[1] Hashimoto K,Saito H,et al.The PPAR gamma ligand,15d-PGJattenuates the severity of cerulean-induced actue pancreatitis pancreatitis.Pancreas,2003, Jul,27(1):58-66
[2] Algul H,Tando Y,Schneider G,et al.Actue Experimental pancreatitis and NF- kappaB/Rel Activation[J].Pancreatology,2002,2(2):503-509.
[3] Ethridge RT,Hashimoto K,Chung DH,et al.Selective inhibition of NF-kappa B attenuates the severity of cerulean-induced actue pancreatitis.J Am Coll Surg,2002,195:497-505.
[4] Schmid RM,Adler G NF-kappaB/rel/IkappaB.Implications in gastrointestinal diseases.Gastroenterology,2000,118:1208-1228.
[5] Perkins ND.The Rel/NF-kappa B family:friend and foe[J].Trends Biochem Sci,2000,25(9):434-440.
[6] Denham W Norman J.The potential role of therapeutic cytokine manipulation in actue pancreatitis[J].Cytokine,2002,20(6):295-303.
[7] Mann DA.The NF-kappa B luciferase mouse:a new tool for real time measurement of NF-kappa B activation in the whole enima.Gut,2002, 51:769-770.
[8] Weighardt, H.S.aiserMoore,R.M.Vabulas,C.J.irschning,H.Wagner,B.Holz-mann 2002.Cutting edge:myeloid differentiation factor 88 deficiency improves resistance against sepsis caused by polymicrobial infection.J.Immunol.169: 2823-2827.
[9] Silverstein,R.2004.D-galactosamine Lethality model:Scopeand Limitations.J. EndotoxinRes.10:147-162.
[10] Qiu J,Hu X,NesiC O,et al.Effect of NF-kappaB oligonucleotidesdes“decoys”on gene expression in P7 rat hippocampus after hypoxia/ischemia[J].J Neuosci Res,2004,77(1):108-118.
[11] Lnae JS,ToddKE,GloorB,et al.Platelet activating factor atagonism,reduce theSy-estmic inflammator rePonse in a murine model of acute Pnacreattiis.J SurgRes,2001,99(2):365-370.
[12] Nomrna JS,FiknGW,SxetonC,ct al.Transgenic animals demonstrate a role for The IL-1 recePtor in regulation IL-1 beta gene exPression at steady-state and during systemic srtess induced by acute Pancreatitis.JSurg Res,1995,63(1) 231-236.
[13] Kusske AM,RongioneAJ,ReberHA,et al.Cytokine and acute ancreatitis.Gas- Rtoenteorlogy,1996,100(2):639一642.
[14] RuaB,Paszkowski A,Esber S,et al.Anti-ICAM-1 antibody modulates late onset Of acinar cell apoptosis and early necrosis in taurocholate-induced experi - mental Acute Pancreatitis.Pancreas,2001,23(l):80-88.
[15] Noman JG,Franz M,RikerA,et al.Rapid elevation of Proinflammatory cytokine during acute Pancreatitis and their origination wihtin the Pancreas.SurgicalFoRum 1994,45:148-156.
[16] HuhgesCB,Henry J,Kotb M,et al.UP-regulation of TNF-αalpha mRNA inthe rat Spleen following induction of Pnacreatitis.J SurgRes,1995,59(6):687-693.
[17] Strieter RM,Kunknel SL,Bone RC.Role of tumor necrosisi factory-alPha in dis- Ease states and inflammation.Crit CARE Med.1993,21(10,suppl):S447-453.
[18] RauB,Paszkowski A,Lillich S,et al.Differential effects of casPase-l/interlekin- 1 bata-converting enzyme on actinar cell necrosis and apoptosis in severe acute Experimental Pancreattiis.Lab Invest,2001,81(7):1001-1013.
[19] GayNJ,Keith FJ.DrosoPhila Toll and IL-l receptor Nature,1991,751,(625)355- 356.
[20] FinkGW,Normna JG.Specific changes in the Pancreatic expression of the in- Terleukin-1 family of genes during experimental acute Pancreariris.Cytokin, 1997,(12):1023-1027.
[21] Norman JG,Fink GW,Denham,w,et al..Tissue-specific cytokine Production dur- Ing experimental acute Pancreattiis.AProbable mechanism for distant organ Dy- sfunction Dig Dis Sei,1997,42(8):1783-1788.
[22] Norman JG,Franz MG,Fink GS,et al.Decreased mortality of severe acute Pan- Creatitis after proXimal cytokine blockade.Ann surg,1995,221(6):625-631.
[23] PaskzowskiAS,Rau,Mayer JM,et al.therapeutic application of casPasel/in- Terleukin-1 bate converting enzyme inhibitor decreased the death rate in severe Acute experimental Pancreatitis.Ann,Sur,2002,235(1):68-76.
[24] Powell JJ,Fearon KC Siriwardena AK,et al.EVidence against a role for Poly- Morphisms at tumor necronsis facftor,interleukin-1 and receptor antagist gene Loci in the regulation of disease severiy in acute Pancreatitis.Surgery,2001,129 (5)633-640.
[25] Bevilacuqe MP,Pober JS,Wheeler ME,et al.IL-1 acts on cultured human vascu Lar endothelium to increase the adhesion of Polymoprhonuclear leuocytes cell line.JClin Invest,1985;2003
[26] tanaka N,Murata A,Uda K,et al.IL-1 recepetor anatgonist modifies changes In vital organs induced by acute necrotic Pancreatitis in an experimental model.Crit Care Med,1995;23:901
[27] Shimada M,Andoh A,Hata K,et al.IL-6 secretion by human pancreatic periaci- nar myofibroblasts in response to inflammatory mediators Immunnol,2002,168 (2):861-6
[28] Geiger,T,Andus,T,Klapproth J,et al.induction of rat acute-phase Protein by in- Terleukin 6 in vivo.Eur J Immunol,1988,(5):717-721.
[29] Leser HG,Gorss,V,Scheibenbogen C,et al.Elevation of serum interleukin-6 con- Centration Precedes acute-Phase response and reflects severity in acute Pancreatitis.Gastroenterology,1991,101(3):782-785.
[30] Inagaki,T,Hoshino M,Haykawa,T,et al.Interleukin-6 is useful marker for Early Prediction of the severity acute Pancreatitis.Panceras,1997,14(l):l-8.
[31] De Beaux AC,Ross JA,Maingy JP,et.al.Proinflammatory cytokine release by PeriPheral blood mononuclear cells form Patient with acute Pancreatitis.BrJ Surg,1996,83(8):1071-1075.
[32] KaW M,Singh S.Serum liPase,C-reactive protein,interleukine-6 levels in ERCP-induced Pancreatitis.Gastroiniest Endosc,2001,54(4):435-440.
[33] Friess H,Shrikhnade S,Riesle E.et al.PhosPholipase A2 isoform in acute pan- creatitis.Ann Surg.2001,233(2):204-212a
[34] AufennagerJ,Samman M,Quintel M,et al.Panceatic PhospholiPase A2 activity In acute Pancreatitis:a Prognostic marker of early identification of patients at ris..Clin Chem Lab Med.2002,40(3):293-297.
[35]杨天德,杨宗城.磷酷酶A2与急性肺损伤.国外医学生理病理科学与临床分册,1997,17(1):24-26.
[36] schrag HJ,Schmitter N,Aufenanger J,et al.Experimental study of a novel phos- Pholipase A2 inhibition in acute Pancreatitis.Br J Surg,1998,85:618-623.
[37] Closa D,Rosello-Catafau J,Martrat A,et al.Changes of systemic Prostacyclin and Thromboxane A2 in sodium taurocholate and cerulean-induced acute Pancreatitis In rats.Dig Dis Sci,1993,38(l):33-38.
[38] Iida T,Yokoi H,Kawarada Y.The effects of a thromboxane A2 synthesis I nhibitor and a Prostaglandin 12 analogue on experimental acute necotizingPancreatitis in rats Pancreas,1998,17(2):140-147
[39] Closa D,et al.Prostanoid and oxygen free radicals in early stages of experimen- tal acute Pancreatitis.Dig Dis Sci,1994,39:1537-1542
[49] Lelcuk S,Alexander,F,Kobzik L,et al.Prostacyclin and TXA2 moderate Postischemic renal failure Surg,1985,98(2):207-212. .