NF-кB在大鼠重症急性胰腺炎肾损伤发病机制中作用的实验研究
摘要
【目的】
探讨核因子-κB(nuclear factor-kappa B,NF-κB)在重症急性胰腺炎(SAP)肾损伤发病机制中的作用,探讨N-乙酰半胱氨酸(N-acety-L-cysteine,NAC)在SAP肾损伤中的治疗作用及其机制。
【方法】
54只SD大鼠随机分为假手术组(SO组),重症急性胰腺炎组(SAP组)及NAC治疗组(NAC组)各组18只。以5%牛磺胆酸钠溶液逆行注入胰胆管制作SAP模型。NAC组于造模后5min经阴茎背静脉注入NAC(200mg/kg)。分别于6h、12h、24h时间点随机处死大鼠。采用免疫组化法检测肾脏组织NF-κB和肿瘤坏死因子(TNF-a)活性,胰腺和肾脏组织做病理切片观察病理变化,同时行血清淀粉酶(AMY)、尿素氮(BUN)、肌酐(Cr)检查。
【结果】
SAP组造模后肾脏组织NF-κB和TNF-α显著升高,各时间点SAP组比SO组明显升高(P<0.05),NAC组比SAP组明显降低(P<0.05);NAC组AMY、BUN、Cr含量与SAP组相比明显降低(P<0.05)。
【结论】
肾脏组织NF-κB活化及TNF-α过度表达可能是SAP并发肾损伤的机制之一,NAC可能抑制肾脏NF-κB活性进而抑制TNF-α的表达,对SAP肾损伤具有一定的保护作用。
[Objective]
To investigate the effect of nuclear factor-kappa B (NF-κB) in the pathogenesis of pancreatitis-associated renal injury in severe acute pancreatitis and the therapeutical effect and mechanism of N-acety-L-cysteine (NAC) in pancreatitis-associated renal injury in severe acute pancreatitis.
[Methods]
Probabilistic Divide 54 SD rats into sham operated group, severe acute panreatitis group and NAC treated group. Injecting 5% sodium taurocholate into pancreatic duct to make SAP model. NAC treated group is to inject NAC (200mg/kg) into vena dorsalis penis 5min after the making of SAP model. Kill the rats at 6h、12h、24h respectively. Detect the activity of NF-κB and TNF-a in kidney by immunohistochemisty. Observe pancreas and kidney by pathological section. Detect scrum amylase. creatinine and urea nitrogen.
[Result]
The level of NF-κB and TNF-a in kidney in SAP group is significant high and the level of SAP group is higher than SO group, the level of NAC group is significant lower than SAP group. the level of scrum amylase. creatinine and urea nitrogen in NAC group is significant lower than SAP group (P<0.05) at each time point.
[Conclusions]
The activation of NF-κB and the over expression of TNF-αin kidney maybe one of the mechanism of pancreatitis-associated renal injury in severe acute pancreatitis. NAC may be able to inhibit the activation of NF-κB and then to inhibit the over expression of TNF-a in kidney. So NAC has some protective effect.
探讨核因子-κB(nuclear factor-kappa B,NF-κB)在重症急性胰腺炎(SAP)肾损伤发病机制中的作用,探讨N-乙酰半胱氨酸(N-acety-L-cysteine,NAC)在SAP肾损伤中的治疗作用及其机制。
【方法】
54只SD大鼠随机分为假手术组(SO组),重症急性胰腺炎组(SAP组)及NAC治疗组(NAC组)各组18只。以5%牛磺胆酸钠溶液逆行注入胰胆管制作SAP模型。NAC组于造模后5min经阴茎背静脉注入NAC(200mg/kg)。分别于6h、12h、24h时间点随机处死大鼠。采用免疫组化法检测肾脏组织NF-κB和肿瘤坏死因子(TNF-a)活性,胰腺和肾脏组织做病理切片观察病理变化,同时行血清淀粉酶(AMY)、尿素氮(BUN)、肌酐(Cr)检查。
【结果】
SAP组造模后肾脏组织NF-κB和TNF-α显著升高,各时间点SAP组比SO组明显升高(P<0.05),NAC组比SAP组明显降低(P<0.05);NAC组AMY、BUN、Cr含量与SAP组相比明显降低(P<0.05)。
【结论】
肾脏组织NF-κB活化及TNF-α过度表达可能是SAP并发肾损伤的机制之一,NAC可能抑制肾脏NF-κB活性进而抑制TNF-α的表达,对SAP肾损伤具有一定的保护作用。
[Objective]
To investigate the effect of nuclear factor-kappa B (NF-κB) in the pathogenesis of pancreatitis-associated renal injury in severe acute pancreatitis and the therapeutical effect and mechanism of N-acety-L-cysteine (NAC) in pancreatitis-associated renal injury in severe acute pancreatitis.
[Methods]
Probabilistic Divide 54 SD rats into sham operated group, severe acute panreatitis group and NAC treated group. Injecting 5% sodium taurocholate into pancreatic duct to make SAP model. NAC treated group is to inject NAC (200mg/kg) into vena dorsalis penis 5min after the making of SAP model. Kill the rats at 6h、12h、24h respectively. Detect the activity of NF-κB and TNF-a in kidney by immunohistochemisty. Observe pancreas and kidney by pathological section. Detect scrum amylase. creatinine and urea nitrogen.
[Result]
The level of NF-κB and TNF-a in kidney in SAP group is significant high and the level of SAP group is higher than SO group, the level of NAC group is significant lower than SAP group. the level of scrum amylase. creatinine and urea nitrogen in NAC group is significant lower than SAP group (P<0.05) at each time point.
[Conclusions]
The activation of NF-κB and the over expression of TNF-αin kidney maybe one of the mechanism of pancreatitis-associated renal injury in severe acute pancreatitis. NAC may be able to inhibit the activation of NF-κB and then to inhibit the over expression of TNF-a in kidney. So NAC has some protective effect.
引文
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1 Zhang XP,Liu DR,Shi Y.Sudy progress in therapeutic effects of traditional Chinese medicine monomer in severe acute pancreatitis.[J]Zhejiang Univ Sci B 2007;8:147-152.
2Chan YC,Leung PS.Acute pancreatitis:animal models and recent advances in basic research.Pancreas 2007;34:1-14.
3 DiMagno MJ,DiMagno EP.New advances in acute pancreatitis.Curr Opin Gastroenterol 2007;23:494-501.
4 KongL,Santiago N,Han TQ, et al. Clinical characteristics and Prognostic factors of severe acute pancreatitis-Worid J Gastroenterol,2004,10(22),3336-3338. 5Pelichovska M, Cvaehovec K, Hoch J.Intensive care for Patients with severe acute Pancreatitis with asignificant multiorgan dysfunction.Rozhl Chir,2004,83(9),443-450.
6 Uchikov A, Shopov A, Markova D.Renal complications in severe acute Pancreatitis.Khirurgiia (sofiia),2003,59(3),9-10.
7Pitchumoni CS,Agarwa LN,Jain NK.Systimic complication of acute pancreatitis.Am J Gastroenterol,1998,83:597-606.
8Rinderknecht H.Faltal pancreatitis,a consequence of excessive leukocyte stimulation.Int J Pancreatol,1998,3:105-112.
9American college of Chest Physicians/Society of C-ritical Care Medicine Consonsus Conference.Definitions for sepsis and organ failure and guidelines for the use of innovative therapies.Crit care Med.1992,20:864-874.
10张延龄.细胞因子与急性胰腺炎.中国实用外科杂志.1999；19(9)；520.
11夏菁,丁一民.急性胰腺炎早期全身炎症反应综合征和细胞因子变化的意义.胰腺病学,2002,2(3)：162-165.
12Formela LJ,Wood LM,Kingsnorth AN.Amelioratio of experimental acute pancreatitis with a potent platelet-activating factor antagonist.Br J Surg,1994,Dec,81(12):1783～1785.
13Mayer JM, Raraty M, Slavin J, et al.Severe acute pancreatitis is related to increased early urinary levels of the activation Peptide of pancreatic phospholipase A(2).Pancreatology,2002, 2(6),535-542.
14Kodedl U,Paul R,Winkler F,et al.Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis.J Neuropathol Exp Neurol,2001,60,1041-1050. 15Schmidt H,Ebeling D.Bauer H.et al Influence of the platelet-activating factor receptor antagonist BN52021 on endotoxin-induced leukocyte adherence in rat mesenteric venules.J Surg Res,1996 Jan,60(1):29-35.
16Liaudet L,Soriano FG,Szabo C.Biology of nitric oxide signaling.Crit Care Med,2000 Apr,28(4 Suppl):N37-52.
17Denham W,Yang J,Wang H.et al Inhibition of p38 mitogen activates kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome.Crit Care Med,2000 Jul,28(7):2567-2572.
18Wink DA,Mitchell JB.Chemical biology of nitric oxide:Insights into regulatory,cytotoxic,and cytoprotective mechanisms of nitric oxide.Free Radic Biol Med,1998 Sep,25(4-5):434-456.
19Wenzel SE.The role of leukotrienes in asthma.Prostaglandins Leukot Essent Fatty Acids,2003,69(2-3):145-155.
20Vinson Gp, Teja R, HO MM, etal.Leukotriene and Blood Vessel Permeability in Airway[J] J Endocrinol,1998,158(40):153-159.
21Foitzik T,HOtz HG,HOtz B, et al.Selective inhibition of cyclooxygenase-2(COX-2) reduces prostaglandin E2 production and attenuates systemic disease sequelae in experimental pancreatitis.Hepatogastroenterology,2003,50(52),1159-1162.
22Jaffray C,Yang J,Carter Get al Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B,mimicking pancreatitis associated adult respiratory distress syndrome. Surery,2000 Aug,128(2):225-231.
23 Eyndhoven WQGamper CJ,Cho E.et al TRAF-3 mRNA splicedeletion variants encode isoforms that induce NF-kappaB activation.Mol Immunol,1999 Jul,36(10):647-658.
24Satoh A,Shimosegawa T,Masamune A.et al Ascitic fluid of experimental severe acute pancreatitis modulates the function of peritoneal macrophages.Pancreas,1999 Oct,19(3):268-275.
[2]Chan YC,Leung PS.Acute pancreatitis animal models and recent advances in basic research.Pancreas 2007;34:1～14.
[3]DiMagno MJ,DiMagno EP.New advances in acute pancreatitis.Curr Opin Gastroenterol 2007;23:494～501.
[4]KongL,Santiago N,Han TQ, et al. Clinical characteristics and Prognostic factors of severe acute pancreatitis.Worid J Gastroenterol,2004,10(22),3336～3338.
[5]Pelichovska M, Cvaehovec K, Hoch J.Intensive care for Patients with severe acute Pancreatitis with asignificant multiorgan dysfunction.Rozhl Chir,2004,83(9),443～450.
[6]Uchikov A, Shopov A, Markova D.Renal complications in severe acute Pancreatitis.Khirurgiia (sofiia),2003,59(3),9～10.
[7]Pitchumoni CS,Agarwa LN,Jain NK.Systimic complication of acute pancreatitis.Am J Gastroenterol,1998,83:597～606.
[8]Rinderknecht H.Faltal pancreatitis,a consequence of excessive leukocyte stimulation.Int J Pancreatol,1998,3:105～112.
[9]American college of Chest Physicians/Society of C-ritical Care Medicine Consonsus Conference.Definitions for sepsis and organ failure and guidelines for the use of innovative therapies.Crit care Med,1992,20:864～874.
[10]张延龄.细胞因子与急性胰腺炎.中国实用外科杂志.1999；19(9)；520.
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13Mayer JM, Raraty M, Slavin J, et al.Severe acute pancreatitis is related to increased early urinary levels of the activation Peptide of pancreatic phospholipase A(2).Pancreatology,2002, 2(6),535-542.
14Kodedl U,Paul R,Winkler F,et al.Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis.J Neuropathol Exp Neurol,2001,60,1041-1050. 15Schmidt H,Ebeling D.Bauer H.et al Influence of the platelet-activating factor receptor antagonist BN52021 on endotoxin-induced leukocyte adherence in rat mesenteric venules.J Surg Res,1996 Jan,60(1):29-35.
16Liaudet L,Soriano FG,Szabo C.Biology of nitric oxide signaling.Crit Care Med,2000 Apr,28(4 Suppl):N37-52.
17Denham W,Yang J,Wang H.et al Inhibition of p38 mitogen activates kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome.Crit Care Med,2000 Jul,28(7):2567-2572.
18Wink DA,Mitchell JB.Chemical biology of nitric oxide:Insights into regulatory,cytotoxic,and cytoprotective mechanisms of nitric oxide.Free Radic Biol Med,1998 Sep,25(4-5):434-456.
19Wenzel SE.The role of leukotrienes in asthma.Prostaglandins Leukot Essent Fatty Acids,2003,69(2-3):145-155.
20Vinson Gp, Teja R, HO MM, etal.Leukotriene and Blood Vessel Permeability in Airway[J] J Endocrinol,1998,158(40):153-159.
21Foitzik T,HOtz HG,HOtz B, et al.Selective inhibition of cyclooxygenase-2(COX-2) reduces prostaglandin E2 production and attenuates systemic disease sequelae in experimental pancreatitis.Hepatogastroenterology,2003,50(52),1159-1162.
22Jaffray C,Yang J,Carter Get al Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B,mimicking pancreatitis associated adult respiratory distress syndrome. Surery,2000 Aug,128(2):225-231.
23 Eyndhoven WQGamper CJ,Cho E.et al TRAF-3 mRNA splicedeletion variants encode isoforms that induce NF-kappaB activation.Mol Immunol,1999 Jul,36(10):647-658.
24Satoh A,Shimosegawa T,Masamune A.et al Ascitic fluid of experimental severe acute pancreatitis modulates the function of peritoneal macrophages.Pancreas,1999 Oct,19(3):268-275.