摘要
目的应用中药新药清胰颗粒(qingyi grains, QYG)对重症急性胰腺炎(severeacute pancreatitis，SAP)大鼠进行治疗，观察模型动物血清淀粉酶变化，对胰腺、肺、肠、肝、肾等组织进行病理组织学检查，观察其治疗效果；观察模型动物血清过氧化物岐化酶（superoxide dismutase, SOD）和丙二醛（malondialdenhyde, MDA）等氧化应激因子变化；观察模型动物各器官核因子κB（NF-κB）和高迁移率族蛋白1（HMGB1）的变化，探讨中药新药清胰颗粒的可能的治疗机制，为日后投入临床使用提供实验依据。
方法根据随机对照试验将Sprague-Dawley大鼠分为：假手术组(sham-operation group, sham)，SAP组，QYG组，每组18只，各组又分别随机分为24h、48h、72h三组，每组6只。采用逆行胰胆管内注射5%牛磺胆酸钠(sodiumtaurocholate，STC)（0.1ml/100g)制备大鼠SAP模型。QYG组于造模后立即给予清胰颗粒溶液（1ml/100g）灌胃治疗，之后每12h重复给药一次，sham组仅予开腹后翻动胰腺，不予胰胆管注射。各组动物于相应时间点处死收集血液和各器官组织，人工碘比色法测定血清淀粉酶，羟胺比色法测定血清总SOD含量，硫代巴比妥酸（TBA）比色法检测血清MDA含量，HE染色观察胰腺、肺、小肠、肝、肾等组织病理，S-P免疫组化法观察胰腺、肺、小肠、肝、肾等组织NF-κBp65以及HMGB1表达变化。
结果
1血清淀粉酶变化
SAP组与QYG组血清淀粉酶水平明显高于sham组；与SAP组比较，QYG组于24h和48h血清淀粉酶明显降低（t=7.929，P=0.000；t=9.847，P=0.000），而与QYG治疗后72h无统计学差异(t =0.769，P=0.460)。
2血清SOD和MDA含量变化
SAP组与QYG组各时间点的血清总SOD含量均明显低于sham组。于QYG治疗后48h和72h，QYG组血清SOD较SAP组明显升高（t =-5.483，P=0.000；t=-4.519，P=0.001），而于治疗后24h无统计学差异(t =-0.747，P=0.472)。SAP组与QYG组各时间点的血清MDA含量均明显高于sham组。于QYG治疗后24h、48h和72h，血清MDA含量均较SAP组明显降低（t =7.128，P=0.000；t =4.544，P=0.001；t =5.501，P=0.001）。
3各器官的病理组织学变化
SAP大鼠胰腺、肺、小肠、肝、肾等组织出现了不同程度的损伤。应用QYG治疗后的大鼠各器官的病理组织学损伤程度较SAP组有所改善。
4各器官NF-κBp65、HMGB1表达变化
SAP大鼠胰腺、肺、小肠、肝、肾等组织NF-κBp65、HMGB1表达增加，应用QYG治疗可不同程度的减少NF-κBp65、HMGB1表达。
结论
1 SAP大鼠血清淀粉酶明显升高，清胰颗粒可以降低急性胰腺炎大鼠高血清淀粉酶血症。
2 SAP大鼠胰腺、肺、小肠、肝、肾等器官出现了不同程度的损伤。应用清胰颗粒治疗后的大鼠，各器官的损伤程度较SAP组改善。中药新药清胰颗粒对急性胰腺炎大鼠的多器官损伤有保护作用。
3 SAP时大鼠机体抗氧化能力减弱，产生大量氧自由基，应用清胰颗粒治疗可提高机体清除氧自由基的能力，降低氧化应激因子的水平。抗氧化作用可能是清胰颗粒治疗急性胰腺炎的可能机制之一。
4 SAP大鼠胰腺、肺、小肠、肝、肾等器官NF-κBp65、HMGB1表达增加，应用清胰颗粒治疗后，大鼠各器官NF-κBp65、HMGB1表达不同程度的减少。清胰颗粒可通过抑制各器官NF-κBp65、HMGB1表达，从而发挥其器官保护作用。
Objective severe acute pancreatitis (SAP) rats were treated by the Chinese newmedicine Qing Yi grains (QYG). To observe the treatment effect, changes of serumamylase in animal models were observed. Pancreas, lung, intestine, liver, kidney wereharvested for pathological examination. Changes of serum peroxide dismutase (SOD)and malondialdehyde (MDA) were observed. Expression changes of nuclear factorκB (NF-κB) and high mobility group protein 1 (HMGB1) in different organs wereobserved to explore the possible treatment mechanism of Chinese new medicine QYGand provide experimental basis for clinical use.
Methods Sprague-Dawley rats were randomly divided into sham operation group,SAP group and QYG group. Each group contained 18 rats and then randomly dividedinto 24h, 48h, 72h three groups, n=6. Rats were prepared by retrograde pancreaticduct injection of 5% sodium taurocholate (STC) (0.1ml/100g) to establish SAP model.QYG group received Qing Yi grains solution (1ml/100g) gavage treatmentimmediately after operation. Repeated administration was given every 12h. Animalsin each group were sacrificed at corresponding time points to collect the blood andorgans to detect serum amylase, T-SOD, MDA, HE staining for pancreas, lung,intestine, liver and kidney, S-P immunochemistry for expressions of organs NF-κBp65and HMGB1.
Results
1 Changes of the serum amylase
Serum amylase levels in SAP group and QYG group were significantly higherthan sham operation group. Compared with SAP group, serum amylase levels in QYG24h and 48h group were significantly decrease (（t =7.929，P=0.000；t =9.847，P=0.000）). They were no significant difference in 72h (t =0.769，P=0.460)
2 Changes of serum SOD and MDA
Serum SOD levels in SAP group and QYG group were significantly lower thanthe sham operation group. At 48h and 72h after QYG treatment, serum SOD levelswere significantly higher than SAP group (t =-5.483，P=0.000；t =-4.519，P=0.001).There were no significant difference at 24h group (t =-0.747，P=0.472). Serum MDAin SAP group and QYG group were significantly higher than sham operation group ateach time point. Compared with SAP group, serum MDA levels of QYG group weresignificantly lower at each time point (t =7.128，P=0.000；t =4.544，P=0.001；t=5.501，P=0.001).
3 Pathological changes in organs
Pathological changes occured in SAP rats’pancreas, lung, intestine, liver, kidney.QYG treatment can improve pathological changes in SAP rats’organs.
4 Changes of NF-κB, HMGB1 expression in organs
NF-κB, HMGB1 expression increased in SAP rats’pancreas, lung, intestine,liver, kidney. Organs NF-κB, HMGB1 expression decreased to different extent afterapplication of QYG treatment.
ConclusioConclusion
1 Serum amylase in SAP rats significantly increases. QYG can reduce high serumhyperamylasemia in SAP rats.
2 In SAP rats, pancreas, lung, small intestine, liver and kidney showed damge invarying degrees. After application of QYG treatment, the extent of organ damageimproves. Traditional Chinese drug Qingyi grains can protect multiple organ damagein rats with acute pancreatitis.
3 In SAP rats, antioxidant capacity is decreased, resulting in a large number of oxygenfree radicals. QYG can increase the antioxidant capacity of body and reduce the levelof oxidative stress factors. Antioxidant effect may be one of the therapy mechanism ofQYG.
4 NF-κB, HMGB1 expression increased in SAP rats’pancreas, lung, intestine, liver,kidney. Organs NF-κB, HMGB1 expression decreased to different extent afterapplication of QYG treatment. QYG can inhibit the organ NF-κB, HMGB1expression, and thus play its role in organ protection.
引文
[1] Ozhan G, Yanar HT, Ertekin C, et al. polymorphisms in tumour necrosis factoralpha (TNFalpha) gene in patients with acute pancreatitis. Mediators Inflamm.2010, 2010:482950
[2] Zhang XP, Zhang L, Xu HM, et al. Application of tissue microarrays to study theinfluence of dexamethasone on NF-kappaB expression of pancreas in rat withsevere acute pancreatitis. Dig Dis Sci. 2008, 53(2):571-80
[3] Paszt A, Eder K, Szabolcs A, et al. Effects of glucocorticoid agonist andantagonist on the pathogenesis of L-arginine-induced acute pancreatitis in rat.Pancreas. 2008, 36(4):369-76
[4] Souza LJ, Shio MT, Molan NA, et al. Acute pancreatitis affects non-parenchymalliver cells by a mechanism dependent on platelet-activating factor. Pancreatology.2007, 7(1):67-73
[5] Xu W, Xia SH, Wang H, et al. role of platelet activating factor in pathogenesis ofacute respiratory distress syndrome. Chin Med J(Engl). 2007, 120(20):1840-4
[6] Scheider L, Hartwig W, Flemming, et al. Protective effects and anti-inflammatorypathways of exogenous calcitonin gene-related peptide in severe necrotizingpancreatitis. Pancreatology. 2009, 9(5):662-9
[7] Zhou X, Xue C. Ghrelin inhibits the development of acute pancreatitis andnuclear factor kappaB activation in pancreas and liver. Pancreas. 2009,38(7):752-7
[8] Shimizu K, Pancreatic stellate cells: molecular mechanism of pancreatic fibrosis.J Gastroenterol Hepatol. 2008, Suppl 1:S119-21
[9] Moreno C, Nicaise C, Gustot T, et al. Chemokine receptor CCR5 deficiencyexacerbates cerulean-induced acute pancreatitis in mice. Am J PhysiolGastrointest Liver Physiol. 2006, 291:G1089-G1099
[10]Hackert T, Pfeil D, Hartwig W, et al. Platelet function in acute experimentalpancreatitis. J Gastrointest Surg. 2007, 11:439-444
[11]Xia SH, Hu CX, Zhao ZL, et al. significance of platelet activating factor receptorexpression in pancreatic tissues of rats with severe acute pancreatitis and effectsof BN52021. World J Gastroenterol. 2007, 13(21):2992-8
[12]Van Minnen LP, Blom M, Timmerman HM, et al. The use of animal models tostudy bacterial translocation during acute pancreatitis. J Gastrointest Surg. 2007,11(5):682-9
[13]Shi C, Andersson R, Zhao X, et al. potential role of reactive oxygen species inpancreatitis-associated multiple organ dysfunction. Pancreatology. 2005,5(4-5):492-500
[14]Czeczot H, Majewska M, Skrzycki M, et al. Activity of GSH-dependent enzymesin blood serum of patients with acute and chronic pancreatitis. Wiad Lek. 2009,62(2):87-92
[15]Khinev S, Tsoneva D, Dafinova K, et al. oxidative stress: unsolved problem inthe complex therapy in critically ill patients. Khirurgiia(Sofiia). 2007, (6):27-31
[16]Bakoyiannis A, Delis S, Dervenis C. Pathophyiology of acute and infectedpancreatitis. Infect Disord Drug Targets. 2010, 10(1):2-4
[17]Escobar J, Pereda J, Arduini A, et al. Role of redox signaling, proteinphosphatases and histone acetylation in the inflammatory cascade in acutepancreatitis therapeutic implications. Inflamm Allergy Drug Target. 2010, [Epudahead of print]
[18]Thareja S, Bhardwaj P, Sateesh J, et al. Variations in the levels of oxidative stressand antioxidante during early acute pancreatitis. Trop Gastroenterol. 2009,30(1):26-31
[19]Criddle DN, Gillies S, Baumgartner-Wilson HK, et al. Menadione-inducedreactive oxygen species generation via redox cycling promotes apoptosis ofmurine pancreatic acinar cells. J Bio; Chem. 2006, 281(52):40485-92
[20]Chen H, Sun YP, Li Y, et al. Hydrogen-rich saline ameliorates the severity ofl-arginine-induced acute pancreatitis in rats. Biochem Biophys Res Commun.2010, 393(2):308-13
[21]Takeo Y, Yoshifumi T, Takashi U, et al. Protective Effect of Caspase Inhibitor onIntestinal Integrity in Experimental Severe Acute Pancreatitis. Journal of SurgicalResearch.2007, 138(2):300-307
[22]Zhang X, Chen L, Luo L, et al. study of the Protective Effects of Dexamethasoneon Ileum Mucosa Injury in Rats With Severe Acute Pancreatitis. Pancreas. 2008,37(3):e74-82
[23]Zhang XP, Xu HM, Jiang YY, et al. Influence of dexamethasone on mesentericlymph node of rats with severe acute pancreatitis. World J Gastroenterol. 2008,14(22):3511-3517
[24]Malleo G, Mazzon E, Genovese T, et al. Etanercept attenuates the developmentof cerulean-induced acute pancreatitis in mice: a comparision with TNF-alphagenetic deletion. Shock. 2007, 27(5):542-551
[25]Zhao M, Xue DB, Zheng B, et al. Induction of apoptosis by artemisinin relievingthe severity of inflammation in caerulein-induced acute pancreatitis. World JGastroenterol. 2007, 13(42):5612-5617
[26]Sha H, Ma Q, Jha RK, et al. Resveratrol ameliorates hepatic injury via themitochondrial pathway in rats with severe acute pancreatitis. Eur J Pharmacol.2008, Epub ahead of print
[27]Cosen-Binker LI, Binker MG, Cosen R, et al. Relaxin prevents the developmentof severe acute pancreatitis. World J Gastroenterol. 2006, 12(10):1558-1568
[28]Xiping Z, Li C, Qifang H, et al. Effects of large dose of dexamethasone oninflammatory mediators and pancreatic cell apoptosis of rats severe acutepancreatitis. World J Gastroenterol. 2007, 13(41):5506-5511
[29]Munoz-Casares FC, Padillo FJ, Briceno J, et al. Melatonin reduces apoptosis andnecrosis induced by ischemia/reperfusion injury of the pancreas. J PinealRes,2006, 40(3):195-203
[30]Zhang W, Wang CY, Yang M, et al. Relationship between the apoptosis andNotch-1 expression in acute pancreatitis. Journal of Huazhong University ofScience and Technology. 2007, 27(1):48-50
[31]Sun NF, Zhang JL. Treatment of severe acute biliary pancreatitis in the elderly byintegrated traditional Chinese and western medicine. Zhongguo Zhong Xi Yi JieHe Za Zhi. 2009, 29(2):126-9
[32]Wang ZC, Xue P, Huang ZW. Effect of an early application of chaiqin chengqidecoction in treating severe acute pancreatitis complicated with acute respiratorydistrees syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009, 29(4):322-4
[33]Wang H, Zheng H, Zhao Z, et al. effect of Chaihu Shihuang soup on blood serumlevel TNF, IL-6 and IL-10 of severe acute pancreatitis (SAP). Zhongguo ZhongXi Yi Jie Za He Zhi. 2009, 34(12):1582-4
[34]Yang XN, Deng LH, Xue P, et al. Non-preventive use of antibiotics in patientswith severe acute pancreatitis treated with integrated traditional Chinese andwestern medicine therapy: a randomized controlled trial. Zhongguo Zhong Xi YiJie He Za Zhi. 2009, 7(4):330-3
[35]Jiang CG. The treatment of acute pancreatitis with Dachengqi decoction in 32cases. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2010, 22(4):249
[36]Ren YY, Gong HL, Tang WF, et al. Dachengqi decoction induces pancreaticacinar cell apoptosis in experimental acute pancreatitis in rats. Zhong Xi Yi JieHe Xue Bao. 2009, 7(7):651-6
[37]Ma Y, Huang ZW, Xia Q, et al. Influence of integrated traditional Chinese andwestern medicine therapy on serum resistin levels in patients with severe acutepancreatitis: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2009,7(12):1134-8
[38]Gong HL, Tang WF, Yu Q, et al. Effect of severe acute pancreatitis onpharmacokinetics of Da-Cheng-Qi decoction components. World J Gastroenterol.2009, 15(47):5992-9
[39]Deng LH, Xiang DK, Xue P, et al. effects of Chai-Qin-Cheng-Qi decoction oncefotaxime in rats with acute necrotizing pancreatitis. World J Gastroenterol.2009, 15(35):4439-43
[40]Tang WF, Wan MH, Huang QR, et al. Effect of Da-Cheng-Qi decoction on thepharmacokinetics of ranitidine in rats. Biomed Chromatogr. 2008, 22(8):851-6
[41]Zhang Y, Shi CX, Li YX. Effect of salviae miltiorrhizae on mRNA expression ofinducible nitric oxide synthase and organ injury in rats with severe acutepancreatitis. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005, 25(11):1012-5
[42]Peng GL, Zhang XY. Effects of Salvia miltiorrhiza on serum levels ofinflammatory cytokines in patients with severe acute pancreatitis. Zhong Xi YiJie He Xue Bao. 2007, 5(1):28-31
[43]Xiping Z, Dijiong W, Jiangfeng L, et al. effects of Salvia miltiorrhizae onICAM-1, TLR4, NF-kappaB and Bax proteins expression in multiple organs ofrats with severe acute pancreatitis or obstructive jaundice. Inflammation.2009,32(4):218-32
[44]Zhang R, Zhang X, Zhang J, Wu J, et al.. efficacy and mechanism of Salviamiltiorrhizae injection in the treatment of rats with severe acute pancreatitis.Inflammation. 2009, 32(2):109-19
[45]Zhang XP, Li ZJ, Liu DR. Progress in research into the mechanism of Radixsalviae miltiorrhizae in treatment of acute pancreatitis. Hepatobiliary PancreatDis Int. 2006, 5(4):501-4
[46]Wang G, Sun B, Zhu H, et al. protective effects of emodin combined withdanshensu on experimental severe acute pancreatitis. Inflamm Res. 2009, [Epubahead of print]
[47]Xiping Z, Jun F, Chengjun, et al. effect of salvia miltiorrhizae on pulmonaryapoptosis of rats with severe acute pancreatitis or obstructive jaundice.Inflammation. 2009, 32(5):287-95
[48]Xiping Z, Yang C, Dijiong W, et al. effects of Salvia miltiorrhiza on intercellularadhesion molecule 1 protein expression in the lungs of rats with severe acutepancreatitis or obstructive jaundice. Pancreas. 2009, 38(3):309-17
[49]Zhang X, Chen L, Zhang J, et al. effect of salvia miltiorrhizae on apoptosis andNF-kappaB p65 expression in the liver of rats with severe acute pancreatitis orobstructive jaundice. J Gastroenterol Hepatol. 2009, 24(5):841-52
[50]Zhang X, Liu D, Wu D, et al. effect of salvia miltiorrhizae on the expressions ofTLR4 protein in the liver of rats with SAP or OJ. Inflammation. 2009,32(3):151-62
[51]Xiping Z, Yan P, Xinmei H, et al.Effects of dexamethasone and Salviamiltiorrhizae on the small intestine and immune organs of rats with severe acutepancreatitis. Inflammation. 2010, [Epub ahead of print]
[52]Xiping Z, Jie Z, Shuyun Y, et al. Influence of Salvia miltiorrhizae on themesenteric lymph node of rats with severe acute pancreatitis or obstructivejaundice. Mediators inflamm. 2009, 2009:675195
[53]Xinping Z, Chuyang L, Jie Z, et al. protection of Salvia miltiorrhizae to thespleen and thymus of rats with severe acute pancreatitis or obstructive jaundice.Mediators inflamm. 2009, 2009:186136
[54]Zhang XP, Feng GH, Zhang J, et al. protective effects of Salvia miltiorrhizae onthe hearts of rats with severe acute pancreatitis or obstruvtive jaundice. J ZhejiangUniv Sci B. 2009, 10(3):193-202
[55]Aho HJ, Koskensalo SM, Nevalainen TJ. Experimental pancreatitis in the rat.Sodium taurocholate-induced acute haemorrhagic pancreatitis. Scand JGastroenterol, 1980,15(4):411-6
[56]Kusske AM, Rongione AJ, Ashley SW, et al. interleukin-10 prevents death inlethal necrotizing pancreatitis in mice. Surgery, 1996, 120(2):284-8
[57]Hofbauer B, Saluja AK, Bhatia M, et al. effect of recombinant platelet-activatingfactor acetylhydrolase on two models of experimental acute pancreatitis.Gastroenterology, 1998, 115(5):1238-47
[58]Inman SR, Srowe NT, Cressman MD, et al. lovastatin preserves renal function inexperimental diabetes. Am J Med Sci. 1999, 317(4):215-221
[59]Zhang XP, Zhang J, Ma ML, et al. Pathological changes at early stage of multipleorgan injury in a rat model of severe acute pancreatitis. Hepatobiliary PancreatDis Int. 2010, 9(1):83-7
[60]Zhang XP, Tian H, Wu DJ, et al. Pathological changes in multiple organs of ratswith severe acute pancreatitis treated by baicalin and octreotide. HepatobiliaryPancreat Dis Int. 2009, 8(1):85-92
[61]Zhang XP, Zhang L, Yang P, et al. Protective effects of Baicalin and Octretide onmultiple organ injury in severe acute pancreatitis. Dig Dis Sci. 2008,53(2):581-91
[62]Sha H, Ma Q, Jha RK. Trypsin is the culprit of multiple organ injury with severeacute pancreatitis. Med Hyhotheses. 2009, 72(2):180-2
[63]Wang YL, Zheng YJ, Zhang ZP, et al. Effects of gut barrier dysfunction and NF-κB activation on aggravating mechanism of severe acute pancreatitis. J Dig Dis.2009, 10(1):30-40
[64]Zou ZD, Zhang ZZ, Wang L, et al. The role of mesenteric lymph in pathogenesisof systemic inflammatory response syndrome and systemic complicationsfollowing severe acute pancreatitis in rats. Zhongguo Wei Zhong Bing Ji Jiu YiXue. 2010, 22(4):206-9
[65]Lutgendorff F, Nijmeijer RM, Sandstrom PA, et al. Probiotics prevent intestinalbarrier dysfunction in acute pancreatitis in rats via induction of ileal mucosalglutathione biosynthesis. PloS One. 2009, 4(2): e4512
[66]Rychter JW, van Minnen LP, Vertheem A, et al. Pretreatment but not treatmentwith probiotics abolishes mouse intestinal barrier dysfunction in acutepancreatitis. Surgery. 2009, 145(2):157-67
[67]Xu JJ, Peng JJ, Hu GC, et al. The role of octahedral montone in colonic barrierprotection in severe acute pancreatitis rats model. Zhonghua Nei Ke Za Zhi. 2010,49(1):49-52
[68]Esrefoglu M, Gui M, Turan F. Comparative effects of several therapatic agents onhepatic damage induced by acute experimental pancreatitis. Dig Dis Sci. 2008,53(5):1303-10
[69]Wang G, Sun B, Gao Y, et al. The effect of emodin-assisted early enteralnutrition on severe acute pancreatitis and secondary hepatic injury. MediatorsInflamm. 2007, 2007:29638
[70]Chen YP, Ning JW, Ji F. Establishment of the critical period of severe acutepacnreatitis-associated lung injury. Hepatobiliary Pancreat Dis Int. 2009,8(5):535-40
[71]Malleo G, Mazzon E, Siriwardena AK, et al. TNF-alpha as a therapeutic target inacute pancreatitis-lessons from experimental models. Scientific World Journal.2007, 7:431-48
[72]Sailai Y, Yu X, Baiheti P, et al. influence of nuclear factor kappaB activation oninflammatory mediators of alveolar macrophages in rats with acute necrotizingpancreatitis. J Investig Med. 2010, 58(1):38-42
[73]Zhou X, Xue C. Ghrelin attenuates acute pancreatitis-induced lung injury andinhibits substance P expression. Am J Med Sci. 2010, 339(1):49-54
[74]Yang T, Mao YF, Liu SQ, et al. Protective effects of the free radical scavengeredaravone on acute pancreatitis-associated lung injury. Eur J Pharmacol. 2010,630(1-3):152-7
[75]Cheng S, Yan WM, Yang B, et al. A crucial role of nitric oxide in acute lunginjury secondary to the acute necrotizing pancreatitis. Hum Exp Toxicol. 2010,29(4):329-37
[76]Chen X, Li SL, Wu T, et al. Proteasome inhibitor ameliorates severe acutepancreatitis and associated lung injury of rats. World J Gastroenterol. 2008,14(20):3249-53
[77]Xiping Z, Jie Z, Qin X, Guanghua F, et al. influence of baicailin and octreotideon NF-kappaB and p-selectin expression in liver and kidney of rats with severeacute pancreatitis. Inflammation. 2009, 32(1):1-11
[78]Krishna GS, Kishore KC, Sriram NP, et al. bilateral renal cortical necrosis inacute pancreatitis. Indian J Nephrol. 2009, 19(3):125
[79]Filipenko PS, Salii IS. Lipid peroxidation in patients with epidemic parotitiscomplicated by pancreatitis. Kin Med (Mosk). 2007, 85(12):52-4
[80]Li ZD, Ma QY, Wang CA. Effect of resveratrol on pancreatic oxygen freeradicals in rats with severe acute pancreatitis. World J Gastroenterol. 2006,12(1):137-40
[81]Esrefoglu M, Gui M, Ates B, et al. Antioxidative effect of melatonin, ascorbicacid and N-acetylcysteine on caerulein-induced pancreatitis and associated liverinjury in rats. World J Gastroenterol. 2006, 12(2):259-64
[82]Esrefoglu M, Gui M, Ates B, et al. Ultrastructural clues for the protective effectof melatonin against oxidative damage in cerulean-induced pancreatitis. J PinealRes. 2006, 40(1):92-7
[83]Szabolcs A, Reiter RJ, Letoha T, et al. Effect of melatonin on the severity ofL-arginine-induced experimental acute pancreatitis in rats. World J Gastroenterol.2006, 12(2):251-8
[84]Long J, Song N, Liu XP, et al. nuclear factor-kappaB activation on the reactiveoxygen species in acute necrotizing pancreatitis rats. World J Gastroenterol. 2005,11(27):4277-80
[85]Jung KH, Hong SW, Zheng HM, et al. melatonin ameliorates cerulean-inducedpancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclearfactor-kappaB in rats. J Pineal Res. 2010, 48(3):239-50
[86]Wang ZC, Xue P, Huang ZW. Effect of an early application of chaiqin chengqidecoction in treating severe acute pancreatitis complicated with acute respiratorydistress syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2009, 29(4):322-4
[87]Zhang MJ, Zhang GL, Yuan WB, et al. treatment of abdominal compartmentsyndrome in severe acute pancreatitis patients with traditional Chinese medincine.World J gastroenterol, 2008, 14(22):3574-8
[88]Zhao YQ, Liu XH, Ito T, et al. protective effects of rhubarb on experimentalsevere acute pancreatitis. World J gastroenterol, 2004, 10(7):1005-9
[89]Zhang XP, Tian H, Wu DJ, et al. pathological changes in multiple organs of ratswith severe acute panceatitis treated by baicalin and octrotide. Hepatobiliarypancreat dis int, 2009, 8(1):85-92
[90]Zhang X, Feng G, Weng W, et al. protective effects of baicalin and octreotide onintestinal mucosa of rats with severe acute pancreatitis. Turk J gastroenterol, 2009,20(2):108-15
[91]Zhang X, Tian H, Wu C, et al. effect of baicalin on inflammatory mediator levelsand microcirculation disturbance in rats with severe acute pancreatitis. Pancreas,2009, 38(7):732-8
[92]Tian H, Zhang X. Wu C, et al. effects of baicalin and octreotide on the serumTNF-alpha level and apoptosis in multiple organs of rats with severe acutepancreatitis. Inflammation, 2009, 32(3):191-201
[93]Xiping Z, Jie Z, Qin X, et al. influence of baicalin and octreotide on NF-kappaBand p-selectin expression in liver and kidney of rats with severe acute pancreatitis.Inflammation, 2009, 32(1):1-11
[94]Li Z, Xia X, Zhang S, et al. up-regulation of toll-like receptor 4 was suppressedby emodin and baicalin in the setting of acute pancreatitis. Biomed pharmacother,2009, 63(2):120-8
[95]Group of pancreas surgery, Chinese society of surgery, Chinese medicalassociation. The guideline of diagnosis and treatment of severe acute pancreatitis.Zhonghua Wai Ke Za Zhi, 2007, 45(11):727-9
[96]Wu RQ, Chen Y, Liu LP. Clinical observation on treatment of severe acutepancreatitis by combined administration of Qingyi decoction and Glauber’s salt.Zhongguo Zhong Xi Yi Jie He Za Zhi, 2007, 27(10):924-6
[97]Liu CG, Leng DY, Liu H. Effect of qingyi decoction in preventingpost-endoscopic retrograde cholangiopancreatography pancreatitis andhyperamylasemia. Zhongguo Zhong Xi Yi Jie He Za Zhi, 2009, 29(7):607-10
[98]Xiao QC, Dui DH, Lan TG. Effects of qingyiⅡgranules on intestinal bacterialtranslocation in rats with acute necrotizing pancreatitis. Zhongguo Zhong Xi YiJie He Za Zhi, 2009, 29(10):905-9
[99]Li YY, Sibaev A, Zhou MZ, et al. the Chinese herbal preparation Qing YiTang(QYT) improves intestinal myoelectical activity and increases intestinaltransit during acute pancreatitis in rodents. Phytother Res, 2007, 21(4):324-31
[100] Yang DY, Duan SB, Aili JT. Effect of qingyi decoction in treating severeacute pancreatitis and its impacts on blood level of tumor necrosis factor-alpha,interleukin-6 and interleukin-8. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009,29(12):1122-4
[101] Li YY, Gao ZF, Dui DH. Therapeutic effect of qingyi decoction andtetrandrine in treating severe acute pancreatitis in miniature pigs and serum druglevel determiniation. Zhongguo Zhong Xi Yi Jie Za Zhi, 2003, 23(11):832-6
[102] Qiu Y, Li YY, Li SG, et al. effect of Qing yitang on activity of intracellularCa2+-Mg2+-ATPase in rats with acute pancreatitis. World J gastroenterol, 2004,10(1):100-4
[103] Li YY, Li XL, Yang CX, et al. effects of tetrandrine and QYT on ICAM-1and SOD gene expression in pancreas and liver of rats with acute pancreatitis.World J gastroenterol, 2003, 9(1):155-9
[104] Yuan H, Jin X, Sun J, et al. Protective effect of HMGB1 A box on organinjury of acute pancreatitis in mice. Pancreas. 2009, 38(2):143-8
[105] Hatada T, Wada H, Nobori T, et al. plasma concentrations and importance ofhigh mobility group box protein in the prognosis of organ failure in patients withdisseminated intravascular coagulation. Thromb Harmost. 2005, 94(5):975-9
[106] Lindstrom O, Tukiainen E, Kylanpaa L, et al. Circulating levels of a solubleform of receptor for advanced glycation end products and high-mobility groupbox chromosomal protein 1 in patients with acute pancreatitis. Pancreas. 2009,38(8):e215-20
[107] Kocsis AK, Szaolcs A, Hofner P, et al. Plasma concentrations ofhigh-mobility group box protein 1, soluble receptor for advanced glycationend-products and circulating DNA in patients with acute pancteatitis.Pancreatology. 2009, 9(4):383-91
[108] Fortunate F, Burgers H, Bergmann F, et al. impaired autolysosome formationcorrelates with lamp-2 depletion: role of apoptosis, autophagy, and necrosis inpancreatitis. Gastroenterology. 2009, 137(1):350-60
[109] Fortunate F, Kroemer G. impaired autophagosome-lysosome fusion in thepathogenesis of pancreatitis. Autophagy. 2009, 5(6):850-3
[110] Sawa H, Ueda T, Takeyama Y, et al. Blockade of high mobility group box-1protein attenuates experimental severe acute pancreatitis. World J gastroenterol.2006, 12(47):7666-70
[111] Yang ZY, Ling Y, Yin T, et al. Delayed ethyl pyrucate therapy attenuatesexperimental severe acute pancreatitis via reduced serum high mobility group box1 levels in rats. World J Gastroenterol. 2008, 14(28):4546-50
[112] Yang R, Shaufl AL, Killeen ME, et al. Ethyl pyruvate ameliorates liverinjury secondary to severe acute pancreatitis. J Surg Res. 2009, 153(2):302-9
[113] Cheng BQ, Liu CT, Li WJ, et al. Ethyl pyruvate improves survival andameliorates distant organ injury in rats with severe acute pancreatitis. Pancreas.2007, 35(3):256-61
[114] Luan ZG, Zhang H, Ma XC, et al. Role of high-mobility group box 1 proteinin the pathogensis of intestinal barrier injury in rats with severe acute pancreatitis.Pancreas. 2010, 39(2):216-23
[115] Viterbo D, Bluth MH, Mueller CM, et al. Mutational characterization ofpancreatitis-assiociated protein 2 domains involved in mediating cytokinesecretion in macrophages and the NF-kappaB pathway. J Immunol. 2008,181(3):1959-68
[116] Xu P, Zhou XJ, Chen LQ, et al. pioglitazone attenuates the severity ofsodium taurocholated-induced severe acute pancreatitis. World J gastroenterol.2007, 13(13):1983-8
[117] Wang YL, Zheng YJ, Zhang ZP, et al. Effects of gut barrier dysfunction andNF-κB activation on aggravating mechanism of severe acute pancteatitis. J DigDis. 2009, 10(1):30-40
[118] Zhang XP, Zhang L, Chen LJ, et al. influence of dexamethasone oninflammatory mediators and NF-kappaB expression in multiple organs of ratswith severe acute pancreatitis. World J Gastroenterol. 2007, 13(4):548-56
[119] Long YM, Chen K, Liu XJ, et al. Cell-permeable Tat-NBD peptideattenuates rat pancreatitis and acinus cell inflammation response. World JGastroenterol. 2009, 15(5):561-9
[120] Kan SH, Huang F, Tang J ,et al. role of intrapulmonary expression ofinducible Nitric oxide synthase gene and nuclear factor kappaB activation insevere pancreatitis-assosiated lung injury. Inflammation. 2010, Epub ahead ofprint
[121] Szabolcs A, Biczo G, Rakonczay Z, et al. simultaneous proteosomeinhibition and heat shock protein induction by bortezomib is beneficialexperimental pancreatitis. Eur J Pharmacol. 2009, 616(1-3):270-4
[1]Takeo Y, Yoshifumi T, Takashi U, et al. Protective Effect of Caspase Inhibitor onIntestinal Integrity in Experimental Severe Acute Pancreatitis[J]. Journal of SurgicalResearch.2007, 138(2):300-307.
[2]Zhang X, Chen L, Luo L, et al. study of the Protective Effects of Dexamethasoneon Ileum Mucosa Injury in Rats With Severe Acute Pancreatitis[J]. Pancreas. 2008,37(3):e74-82.
[3]Zhang XP, Xu HM, Jiang YY, et al. Influence of dexamethasone on mesentericlymph node of rats with severe acute pancreatitis[J]. World J Gastroenterol. 2008,14(22):3511-3517.
[4]Malleo G, Mazzon E, Genovese T, et al. Etanercept attenuates the development ofcerulean-induced acute pancreatitis in mice: a comparision with TNF-alpha geneticdeletion[J]. shock. 2007, 27(5):542-551.
[5]Zhao M, Xue DB, Zheng B, et al. Induction of apoptosis by artemisinin relievingthe severity of inflammation in caerulein-induced acute pancreatitis[J]. World JGastroenterol. 2007, 13(42):5612-5617.
[6]Sha H, Ma Q, Jha RK, et al. Resveratrol ameliorates hepatic injury via themitochondrial pathway in rats with severe acute pancreatitis[J]. Eur J Pharmacol.2008, Epub ahead of print.
[7]Cosen-Binker LI, Binker MG, Cosen R, et al. Relaxin prevents the development ofsevere acute pancreatitis[J]. World J Gastroenterol. 2006, 12(10):1558-1568.
[8]Xiping Z, Li C, Qifang H, et al. Effects of large dose of dexamethasone oninflammatory mediators and pancreatic cell apoptosis of rats severe acutepancreatitis[J]. World J Gastroenterol. 2007, 13(41):5506-5511.
[9]Dang SC, Zhang JX, Mao ZF, et al. Dynamic changes of IL-2/IL-10, sFas andexpression of Fas in intestinal mucosa in rats with acute necrotizing pancreatitis[J].World J Gastroenterol. 2008, 14(14):2246-2250.
[10]Xiping Z, Li C, Miao L, et al. Protecting effects of dexamethasone on thymus ofrats with severe acute pancreatitis[J]. Mediators Inflamm, 2007, 2007:72361.
[11]Peng Y, Gallagher SF, Haines K, et al. Nuclear factor-kappaB mediates Kupffercell apoptosis through transcriptional activation of Fas/FasL[J]. J SurgRes,2006,130(1):58-65.
[12]Peng Y, Sigua CA, Gallagher SF, et al. Protein kinase C-zeta is critical inpancreatitis-induced apoptosis of Kupffer cells[J]. J GastrointestSurg,2007,11(10):1253-1261.
[13]Peng Y, Sigua CA, Rideout D, et al. Deletion of toll-like receptor-4 downregulatesprotein kinase C-zeta and attenuates liver injury in experimental pancreatitis[J].Surgery. 2008, 143(5):679-685.
[14]Savkovic V, Gantzer H, Reiser U, et al. Clusterin is protective in pancreatitisthrough anti-apoptotic and anti-inflammatory properities[J]. Biochem Biophys ResCommun. 2007, 356(2):431-437.
[15]Criddle DN, Gillies S, Baumgartner-Wilson HK, et al. Menadione-inducedreactive oxygen species generation via redox cycling promotes apoptosis of murinepancreatic acinar cells[J]. J Biol Chem,2006,281(52):40485-40492.
[16]Munoz-Casares FC, Padillo FJ, Briceno J, et al. Melatonin reduces apoptosis andnecrosis induced by ischemia/reperfusion injury of the pancreas[J]. J Pineal Res,2006,40(3):195-203.
[17]Yu JH, Kim DG, Kim H. Diphenyleneiodonium suppresses apoptosis incerulean-stimulated pancreatic acinar cells[J]. Int Biochem CellBiol,2007,39(11):2063-2075.
[18]Kubisch CH, Sans MD, Arumugam T, et al. Early activation of endoplasmicreticulum stress is associated with arginine-induced acute pancreatitis[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 291(2):238-245.
[19]Suyama K, Ohmuraya M, Hirota M, Ozaki N, et al. C/EBP homologous protein iscrucial for the acceleration of experimental pancreatitis[J]. Biochem Biophys ResCommun. 2008, 367(1):176-182.
[20]Zhang W, Wang CY, Yang M, et al. Relationship between the apoptosis andNotch-1 expression in acute pancreatitis[J]. Journal of Huazhong University ofScience and Technology. 2007, 27(1):48-50.