胰腺微循环障碍加重过程中血管内皮生长因子的表达意义
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摘要
目的：构建大鼠急性胰腺炎从水肿型向坏死型加重的模型,研究血管内皮生长因子(vascular endothelial growth factor, VEGF)在血清、胰腺组织中的表达水平与胰腺微循环障碍加重过程的关系及意义。
方法：实验随机分为假手术对照组(N)、急性水肿型胰腺炎组(AEP)及急性坏死型胰腺炎组(ANP)。建模后6h、12h、24h,分别采用ELISA法检测各组血清中的VEGF、TNF-a及AMY含量和检测胰腺组织中VEGF蛋白免疫组化的表达情况,光镜观察胰腺病理改变情况,比较分析其变化规律。
结果：1、建模后6h、12h和24h,ANP组及AEP组血清中VEGF、TNF-a与AMY的平均含量均明显升高,与N组比较有显著性差异(p<0.05；ANP组与AEP组之间具有显著性差异(p<0.05)；但建模后24h的AEP组的VEGF平均含量与ANP组的没有显著性差异(p>0.05)；血清VEGF与TNF-a正相关(P＜0.05)2、AEP组胰腺病理表现为：间质充血、水肿,粒细胞浸润,散在的腺泡坏死灶,各时点的病理变化不明显；ANP组建模后6h出现胰腺间质水肿、出血,实质灶性坏死,脂肪坏死,大量红细胞沉积,部分胰管破坏,间质微血管破裂,在建模后12h和24h明显加重,大量红细胞溢出,坏死更明显,并微血管血栓形成及组织自溶。3、在各时点的AEP组和ANP组胰腺组织中VEGF蛋白免疫组化染色评分均增高,与N组比较有显著性差异(P<0.05)；在AEP组和ANP组胰腺组织中VEGF蛋白免疫组化染色评分变化情况不全一致,各时点的AEP组VEGF评分持续增高,而ANP组在建模后6h以后的组别均呈减少趋势,各时点的评分有显著性差异(p<0.05)；在建模后6hANP组VEGF评分显著增高,与AEP组比较表达更明显,有显著性差异(p<0.01),但建模后12h和24h的ANP组比AEP组的VEGF评分减少,均有显著性差异(p<0.05)。
结论：实验模型中：血清VEGF与全身炎症反应正相关；在水肿型胰腺炎模型中胰腺组织VEGF免疫组化染色评分与全身炎症反应正相关,表明了胰腺的微循环障碍导致的水肿型胰腺炎与VEGF表达增高有关；但在胰腺微循环障碍加重的模型中胰腺组织VEGF免疫组化染色评分与胰腺病理评分负相关,可能表明胰腺微循环障碍持续的加重,导致胰腺组织及血管内皮细胞损伤严重,同时加速激活、释放各种蛋白水解酶,微循环出凝血机制异常广泛血栓形成,预示了胰腺的坏死病变将难以逆转。
Objective: To establish the model of acute pancreatits aggravating from edema to necrosis in rats and to investigate the relationship between the expressions of vascular endothelial growth factor (VEGF) in serum and pancreas and the aggravating course of microcirculation in pancreas.
Methods: Rats were randomly divided into three groups:sham normal group (N), acute edema pancreatits (AEP) and acute necrosis pancreatits (ANP). In 6h,12h and 24h after modeling, the serum VEGF、TNF-a and AMY were measured by ELISA, the expressions of VEGF protein in pancreas were detected by immunohistochemistry and the pancreas histology was detected by microscope.
Results:1. The scores of VEGF protein in pancreas in AEP and ANP group by immunohistochemistry added in all time points compared with N group (P<0.05); The changes of the scores of VEGF protein in pancreas in AEP and ANP group by immunohistochemistry were not accordant completely, VEGF scores in AEP group increased persistently in all time points, while the scores decreased after 6h in ANP group, which were significantly different in all time points(P<0.05);VEGF scores in ANP group increased markedly in 6h, which were more distinct compared with AEP group(P＜0.05), yet the scores in ANP group reduced compared with AEP group in 12h and 24h(P<0.05).2. In 6h,12h and 24h after modeling, the serum VEGF、TNF-a and AMY in ANP and AEP group obviously increased, which were of significant difference compared with N group(P<0. 05); there was significant different between ANP and AEP group (P<0.05); but the VEGF expression in ANP and AEP group in 24h was of no significant difference (P> 0.05).3.The pathology of pancreas in AEP group were:The interstitium congestion and edema, neutrophils infiltration, diffuse necrosis of acinus, the changes of different time points were not evident; in ANP group, interstitium edema and haemorrhage, parenchyma focal necrosis, adiponecrosis, large erythrocytes sedimentation, some pancreatic ducts destruction and interstitium microvessels break were observed in 6h after modeling, the changes were more obvious in 12h and 24h, of which many erythrocytes overflowed, microvessel thrombosis and tissue autolyzed.
Conclusions: the serum VEGF is associated with systemic inflammation response (SIRS); in edema pancreatits models, the VEGF immunohistochemistry scores are positive correlated with SIRS, while in models of aggravating pancreatic mi crocirculation, the VEGF immunohistochemistry scores are negative correlated with SIRS, demonstrating that the aggravating pancreatic microcirculation may cause severe injuries of pancreatic tissues and vascular endothelial cells, meanwhile accelerate the activating and releasing of various proteolytic enzymes, extensive thrombosis due to the abnormal mechanism of thrombus and hemostasia in microcirculation, indicating the pancreatic necrosis are hardly reversed.
方法：实验随机分为假手术对照组(N)、急性水肿型胰腺炎组(AEP)及急性坏死型胰腺炎组(ANP)。建模后6h、12h、24h,分别采用ELISA法检测各组血清中的VEGF、TNF-a及AMY含量和检测胰腺组织中VEGF蛋白免疫组化的表达情况,光镜观察胰腺病理改变情况,比较分析其变化规律。
结果：1、建模后6h、12h和24h,ANP组及AEP组血清中VEGF、TNF-a与AMY的平均含量均明显升高,与N组比较有显著性差异(p<0.05；ANP组与AEP组之间具有显著性差异(p<0.05)；但建模后24h的AEP组的VEGF平均含量与ANP组的没有显著性差异(p>0.05)；血清VEGF与TNF-a正相关(P＜0.05)2、AEP组胰腺病理表现为：间质充血、水肿,粒细胞浸润,散在的腺泡坏死灶,各时点的病理变化不明显；ANP组建模后6h出现胰腺间质水肿、出血,实质灶性坏死,脂肪坏死,大量红细胞沉积,部分胰管破坏,间质微血管破裂,在建模后12h和24h明显加重,大量红细胞溢出,坏死更明显,并微血管血栓形成及组织自溶。3、在各时点的AEP组和ANP组胰腺组织中VEGF蛋白免疫组化染色评分均增高,与N组比较有显著性差异(P<0.05)；在AEP组和ANP组胰腺组织中VEGF蛋白免疫组化染色评分变化情况不全一致,各时点的AEP组VEGF评分持续增高,而ANP组在建模后6h以后的组别均呈减少趋势,各时点的评分有显著性差异(p<0.05)；在建模后6hANP组VEGF评分显著增高,与AEP组比较表达更明显,有显著性差异(p<0.01),但建模后12h和24h的ANP组比AEP组的VEGF评分减少,均有显著性差异(p<0.05)。
结论：实验模型中：血清VEGF与全身炎症反应正相关；在水肿型胰腺炎模型中胰腺组织VEGF免疫组化染色评分与全身炎症反应正相关,表明了胰腺的微循环障碍导致的水肿型胰腺炎与VEGF表达增高有关；但在胰腺微循环障碍加重的模型中胰腺组织VEGF免疫组化染色评分与胰腺病理评分负相关,可能表明胰腺微循环障碍持续的加重,导致胰腺组织及血管内皮细胞损伤严重,同时加速激活、释放各种蛋白水解酶,微循环出凝血机制异常广泛血栓形成,预示了胰腺的坏死病变将难以逆转。
Objective: To establish the model of acute pancreatits aggravating from edema to necrosis in rats and to investigate the relationship between the expressions of vascular endothelial growth factor (VEGF) in serum and pancreas and the aggravating course of microcirculation in pancreas.
Methods: Rats were randomly divided into three groups:sham normal group (N), acute edema pancreatits (AEP) and acute necrosis pancreatits (ANP). In 6h,12h and 24h after modeling, the serum VEGF、TNF-a and AMY were measured by ELISA, the expressions of VEGF protein in pancreas were detected by immunohistochemistry and the pancreas histology was detected by microscope.
Results:1. The scores of VEGF protein in pancreas in AEP and ANP group by immunohistochemistry added in all time points compared with N group (P<0.05); The changes of the scores of VEGF protein in pancreas in AEP and ANP group by immunohistochemistry were not accordant completely, VEGF scores in AEP group increased persistently in all time points, while the scores decreased after 6h in ANP group, which were significantly different in all time points(P<0.05);VEGF scores in ANP group increased markedly in 6h, which were more distinct compared with AEP group(P＜0.05), yet the scores in ANP group reduced compared with AEP group in 12h and 24h(P<0.05).2. In 6h,12h and 24h after modeling, the serum VEGF、TNF-a and AMY in ANP and AEP group obviously increased, which were of significant difference compared with N group(P<0. 05); there was significant different between ANP and AEP group (P<0.05); but the VEGF expression in ANP and AEP group in 24h was of no significant difference (P> 0.05).3.The pathology of pancreas in AEP group were:The interstitium congestion and edema, neutrophils infiltration, diffuse necrosis of acinus, the changes of different time points were not evident; in ANP group, interstitium edema and haemorrhage, parenchyma focal necrosis, adiponecrosis, large erythrocytes sedimentation, some pancreatic ducts destruction and interstitium microvessels break were observed in 6h after modeling, the changes were more obvious in 12h and 24h, of which many erythrocytes overflowed, microvessel thrombosis and tissue autolyzed.
Conclusions: the serum VEGF is associated with systemic inflammation response (SIRS); in edema pancreatits models, the VEGF immunohistochemistry scores are positive correlated with SIRS, while in models of aggravating pancreatic mi crocirculation, the VEGF immunohistochemistry scores are negative correlated with SIRS, demonstrating that the aggravating pancreatic microcirculation may cause severe injuries of pancreatic tissues and vascular endothelial cells, meanwhile accelerate the activating and releasing of various proteolytic enzymes, extensive thrombosis due to the abnormal mechanism of thrombus and hemostasia in microcirculation, indicating the pancreatic necrosis are hardly reversed.
引文
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[25]vander Flier M,van Leeuwen HJ,van Kessel KP,et al. Plasma vascular endothelial growth factor in severe pancreatitis.J Shock,2005,23 (1):35238.
[26]Pickkers P,Sprong T,Eij K,et al. Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability.J Shock,2005,24 (6):5082512.
[27]vander Flier M,Stockhammer G,Vonk GJ,et al. Vascular endothelial growth factor in bacterial meningitis:detection in cerebrospinal fluid and localization in postmortem brain J Infect Disease,2001,183 (1):1492153.
[28]Kinnala PJ, Kuttila KT, Gronroos JM, et al. Pancreatic tissue perfusion in experimental acute pancreatitis. Eur J Surg,2001,167 (9):689-694.
[29]Mitchell RM, Byrne MF, Baillie J. Pancreatitis.Lancet,2003,361 (9367):1447-1455.
[30]ZHOU ZG,CHEN YD.Influencing factors of pancreatic microcirculatory impairment in acute pancreatitis.J World Gastroenterol,2002,8:406-412.
[31]Reinders ME, Sh M, Izawa A, et al. Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J Clin Invest,2003,112(11):1655-1665.
[32]Cheng HW, James AF, Foster RR,et al.VEGF activates receptor operated cation channels in human microvascular endothelial cells.J Arterioscler,Thromb Vasc Biol,2006,26(8):176821776.
[2]Tischer E, Mitchell R, Hartman T, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing.J Biol Chem,1991,266 (6):119472 11954.
[3]Kinnala PJ,Kuttila KT,Gronroos JM,et al.Pancreatic tissue perfusion in experimental acute pancreatitis. Eur J Surg,2001,167 (9):689-694.
[4]Beattie GC,Hardman JG,Redhead D,et al.Evidence for a central role for selective mesenteric angiography in the management of the major vascular complications of pancreatitis. Am J Surg,2003,185 (2):96-102.
[5]Aho HJ, Koskensalo SML, Nevaluinen TJ, Experimental pancreatitis in the rat isodium taurocholate induced acute haemorrhagic pancreatitis.Scand.J Gastroenterol,1980; 15: 411-41
[6]Yan LN, Liu XB, Tan JS, et al. Effect of haemorrheological changes in the transition of edematous pancreatitis to necrosis. J Asian Surgery,1995; 18(2):106
[7]Schmidt J,Rattner DW,Lewanddrowski K,et al.A better model of acute pancreatitis for evaluating therapy.J Ann Surg,1992,215:44-56
[8]Friess H,Yamanka Y, Buchler M,et al.Enhanced expression of transforming growth factor-beta isoforms in pancreatic cancer correlates with decreasd survival.J Gastroenterology,1993,105:1846-1856.
[9]Torhorst J,Bucher C,Kononen J, et al. Tissue microarrays for rapid linking of molecular changes to clinical endpoints.Am J patlol,2001,159(6):2249-2256.
[10]Enjoji M, Nakamuta M, Yamaguchi K,et al.Clinical significance of serum levels of vascular endothelial growth factor and its receptor in biliary disease and carcinoma .World J Gastroenterol,2005,11 (8):11672-1171.
[11]Plouet J,Moro F,Bertagnolli S,et al.Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect.J Biol Chem,1997,272:13390-13396.
[12]Gldberg MA, Schneider TJ.Similarities between the oxygen sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin.J Biol Chem,1994,269 (6):43552 4359.
[13]Brouckaert P et al, tumor necrosis factor and the systemic inflammatory response syndrome. J Curr-Top Microbiol Immune 1996;216:167-187
[14]Connolcy DT.Vascular permeability factor: a unique regulator of blood vessel function. J CellBiochem,1999,47(3):2192223.
[15]Abrahamov D, Erez E,TamarizM,et al. Plasma vascular endothelial growth factor level is a predictor of the severity of postoperative capillary leak syndrome in neonates undergoing cardiopulmonary bypass.J Pediatr Surg Int,2002,18 (1):54-59.
[16]Eibl G, Buhr HJ, Foitzik T. Therapy of microcirculatory disorders in severe acute pancreatitis:what mediators should we block.J Intens Care Med,2002,28 (2):139-146.
[17]Clauss M. Molecular biology of the VEGF and VEGF receptor family. J Seminal Thromb Hemost,2000,26(5):5612569.
[18]vander Flier M,Stockhammer G,Vonk GJ,et al.Vascular endothelial growth factor in bacterial meningitis:detection in cerebrospinal fluid and localization in postmortem brain.J Infect Disease,2001,183 (1):149-153.
[19]ZHOU ZG,CHEN YD.Influencing factors of pancreatic micro-circulatory impairment in acute pancreatitis. World J Gastroenterol,2002,8:406-412.
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