清胰颗粒对重症急性胰腺炎大鼠肠黏膜屏障的保护作用
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摘要
目的:建立大鼠重症急性胰腺炎模型,并探讨中药清胰颗粒对重症急性胰腺炎(severe acute pancreatitis,SAP)大鼠肠黏膜屏障功能的影响及其作用机制方法:选取健康雄性Wistar大鼠分为正常组、假手术组和模型A、B、C组,采用牛磺胆酸钠胰胆管逆行注射方法建立SAP动物模型,假手术组和模型A、B、C组大鼠胆胰管插管,分别逆行注射生理盐水和2%、3.5%、5%的牛磺胆酸钠,观察各组死亡率和胰腺损伤程度;在SAP大鼠模型稳定后选取150只健康雄性Wistar大鼠,随机分为3组,分别为假手术组、模型组和治疗组。模型组和治疗组均采用胆胰管逆行注射3.5%牛磺胆酸钠建立SAP模型,治疗组于造模前2h、造模后6h、18h、30h和42h分别给予清胰颗粒灌胃,模型组和假手术组以同样的方法分别给与中药安慰剂和生理盐水灌胃。各组动物分别于造模前、造模后6h、12h、24h、48h取腹主动脉血行淀粉酶和二胺氧化酶的检测,取胰腺组织和末端回肠行HE染色和病理学评分,同时测量肠绒毛高度、黏膜厚度,并应用免疫组化方法检测小肠黏膜紧密连接蛋白Claudin-1的表达。
结果:
1.假手术组无死亡记录,模型A、B、C组在术后72h死亡率分别为20%、50%、70%;模型B组淀粉酶造模后6h最高达9023.0±1924.5 U/L,以后随时间逐渐下降,在72h降为2245.3±271.6仍高于假手术组和正常组且有统计学意义(p<0.05);镜下所见模型B组胰腺间质水肿;红细胞漏出;炎细胞浸润。腺泡细胞水肿;点片状出血;灶性变性、坏死;部分导管扩张。病理学评分模型B组与假手术组各时点比较9.89±2.11 vs 1.27±1.13、10.25±1.98 vs 1.32±1.28、11.71±2.11 vs 1.03±0.11、13.85±1.05 vs 1.01±0.19、13.89±0.89 vs 0.98±0.07均有显著性差异。
2.模型组大鼠精神萎靡、竖毛、少动倦卧;治疗组大鼠精神状态较好、活动较多、排便次数增加、肛周污染明显。假手术组无死亡记录,治疗组SAP大鼠死亡率低。模型和治疗组6h、12h、24h、48h的死亡率分别为0%(0/10)、20%(2/10)、40%(4/10)、50%(5/10)和0%(0/10)、20%(2/10)、30%(3/10)、30%(3/10);治疗组24h死亡率低于模型(p<0.05)
3.假手术组淀粉酶在造模后6h一过性升高,随后恢复正常;模型组淀粉酶造模后6h最高,以后随时间逐渐下降,但在48h仍高于假手术组(p<0.05);与模型比较,治疗组造模后12h降低开始有统计学意义(p<0.05),48h与假手术组比较无差异
4.假手术组血清DAO水平在造模前后无变化(p>0.05);治疗组血清DAO水平在造模后24 h和48 h较模型组降低有显著性差异(p<0.05)
5.假手术组术后6h可见胰腺腺泡细胞轻度水肿、无出血及坏死。模型组可见胰腺间质水肿,红细胞漏出,炎细胞浸润,腺泡细胞水肿,点片状出血,灶性变性、坏死,部分胰腺导管扩张,随时间推移胰腺组织病理学评分逐渐加重。治疗组24h以上改变均减轻病理学评分降低有统计学意义。
6.光镜下假手术组肠黏膜绒毛结构完整,上皮呈高柱状,间质无水肿、无中性粒细胞浸润。模型组肠黏膜结构损伤明显,并呈进行性变化,尤以制模24h最明显,可见大鼠回肠间质水肿并有点状出血,血管淋巴管均扩张,还可见大量中性粒细胞浸润伴淋巴滤泡增生,肠绒毛水肿增粗,高度缩短,顶端上皮有片状坏死、脱落,杯状细胞减少,排列紊乱;黏膜厚度变薄,黏膜腺体排列稀疏,腺体减少;中药清胰颗粒治疗组在造模12h时与模型组相比病理损伤有所减轻,表现为炎症细胞浸润减少,绒毛损伤脱落减少,黏膜厚度及绒毛高度均有改善,造模后24 h开始有显著的差异。术后48 h各指标均接近正常值
7.各组小肠黏膜claudin-1均分布于肠上皮紧密连接的细胞膜(包括细胞膜顶部),膜内近侧的胞质区少量染色,为棕黄色染色颗粒,胞核及核膜无表达。假手术Claudin-1蛋白在细胞膜表达且为强阳性;与假手术组比较,模型组claudin-1表达明显下降p<0.05);与模型组比较,治疗组造模后各时间点Claudin-1表达升高且有统计学意义(p<0.05)
结论:
1.应用静脉留置针导管经十二指肠乳头逆行注射3.5%牛磺胆酸钠(0.1ml/100g体重、注射速度为0.15ml/min)诱导的SAP大鼠动物模型是Aho法制备SAP大鼠模型的改良,是进行SAP中药临床研究科研较为理想的动物模型
2.早期应用清胰颗粒能够改善SAP大鼠胰腺组织的损伤,减轻肠黏膜和肠绒毛萎缩,提高肠道紧密连接蛋白Claudin-1水平的表达水平,降低肠黏膜通透性保护肠屏障,降低死亡率。
Objectives:To create the animal model with severe acute pancreatitis which can adapt to scientific research,and to investigate the effects of Qingyi granules on the intestinal mucosa barrier in rats with severe acute pancreatitis(SAP). Methods:Healthy male Wistar rats were divided into normal group,sham operation group and model A,B,C group,Severe acute pancreatitis model was induced by retrograde injection of sodium deoxycholate into the biliopancreatic duct in rats.,the sham operation group and model A,B,C Group rat,respectively,by retrograde injection of saline and 2%,3.5%,5%sodium deoxycholate,observed mortality and the extent of pancreatic injury;then 150 healthy male Wistar rats were randomly divided into 3 groups:sham-operation group,model group and treatment group.The model group and the treatment group were retrograde biliopancreatic injection of 3.5%sodium deoxycholate to create SAP model,and treatment group were given orally Qingyi granules at 2 hours before induction of SAP,at 6h,18h,30h and 42h after SAP,the model group were given placebo in the same way.The levels of serum amylase and diamine oxidase were determined,the histopathology of pancreatic and terminal ileum tissue were examined by hematoxylin and eosin(HE) staining at 0h,6 h、12 h、24 h and 48h after SAP and histologic assessment was performed.At the same time,we measured intestinal villus height,mucosal thickness and detection of small intestinal mucosal tight junction protein Claudin-1 expression by immunohistochemistry.
Results:
1.Sham-operated group was no death records,the mortality of models A,B,C groups after 72h were 20%,50%,70%;the level of amylase in model B group after 6 h up to 9023.0±1924.5 U/L and was a gradual decline over time,after 72 h reduced to 2245.3±271.6 U / L,but still higher than the sham-operated group and the normal group and were statistically significant(p <0.05);In model B group,the pancreas showed that interstitial edema,red blood cell leakage,inflammatory cell infiltration, acinar cells edema,point sheet hemorrhage,focal degeneration and necrosis. Pathology score of model B group and sham-operated group in every time point 9.89±2.11 vs 1.27±1.13,10.25±1.98 vs 1.32±1.28,11.71±2.11 vs 1.03±0.11, 13.85±1.05 vs 1.01±0.19,13.89±0.89 vs0.98±0.07 were showed difference significantly.
2.Model rats showed apathetic,erect hair,lying tired paucimobilis;In treated group rats showed better mental state,activities of large increase in the number of defecation,perianal obvious pollution.Sham-operated group without death records, the mortality of rats with SAP were lower in treatment group.The mortality of rats with SAP in model group and treatment group were 0%(0/10),20%(2/10)、40% (4/10)、50%(5/10) and 0%(0/10)、20%(2/10)、30%(3/10)、30%(3/10) respectively.The mortality of the treatment group in 24 h was lower than the model group(p <0.05).
3.The level of amylase in sham-operated group appeared transient increase after model 6h and then returned to normal;In model group model,the level of amylase was highest after model 6 h,and gradually decreased with time,but in the 48 h was still higher than sham-operated group(p <0.05);Compared with the model group,the level of amylase in treatment group 12 h after began to reduce(p <0.05),in 48 h they showed no differences
4.The level of serum DAO in sham-operated group before and after operation was no change (P> 0.05);The levels of serum DAO in treatment group after 24 h and 48 h was lower than the model group(p <0.05).
5.After model 6h in sham-operated group acinar cells can be seen with mild edema, no bleeding and necrosis.In model group,the pancreas was Observated that interstitial edema,red blood cell leakage,inflammatory cell infiltration,acinar cells,edema, patchy hemorrhage point,focal degeneration and necrosis,and some glandular dilatation,the pathology score of pancreatic tissues gradually increased.The changes with 24 h and more in treatment group was decreasing,which was significance in statistics.
6.Under light microscope,the villi structural integrity of the intestinal mucosa in sham-operated group was showed a high columnar epithelium,interstitial edema,no neutrophil infiltration.In model group,the structure of intestinal mucosa was damaged significantly in a progressive manner,particularly in the most obvious mold 24h,showing interstitial edema in rat ileum and a bit like bleeding,the expansion of lymphatic vessels,but was also showed that a large number of neutrophil infiltration with lymphoid follicular hyperplasia,thickening of intestinal villi edema,high degree of shortening,there was patchy epithelial necrosis of the top,falling,goblet cell decrease with disorder;mucosal thickness were becamed thinner,mucosa with sparse glands,glands reduced;When compared with the model group,the treatment of traditional Chinese medicine Qing Yi granules 12h in the model group reduced the pathological damage,manifested as reduced inflammatory cell infiltration,villous injury to reduce shedding,mucosal thickness and villous height were improved,24h after the beginning of the model with significant differences.48h after the operation, the indicators were close to normal.
7.The claudin-1 of Small intestinal mucosa in each group were distributed in intestinal epithelial tight junction of cell membranes(including the cell membrane at the top),cytoplasmic area of membrane proximal appeared a small amount of staining, with staining brown granules,but nucleus and nuclear membrane without expression. The Claudin-1 protein of sham-operation group expression in the cell membrane and was strongly positive;Compared with the sham-operated group,the expression of claudin-1 was low in model group(p <0.05);Compared with the model group,the Claudin -1 of treatment group at different time points after model expression was higher(p < 0.05)
Conclusion:
1.Application of intravenous catheter system from duodenal catheter by retrograde cholangiopancreatography injection of 3.5%sodium taurocholate to establish SAP model(0.1ml/100g weight,speed of injection 0.15ml/min) is a improved model from preparation Aho SAP method,and is a good research animal model for SAP.
2.Early application of Qingyi granules can improve the damage of pancreatic tissue in rats with SAP,reduce the intestinal mucosa and intestinal villus atrophy,improve intestinal tight junction protein Claudin-1 expression levels,reduce the permeability of intestinal mucosa,and decrease mortality.
结果:
1.假手术组无死亡记录,模型A、B、C组在术后72h死亡率分别为20%、50%、70%;模型B组淀粉酶造模后6h最高达9023.0±1924.5 U/L,以后随时间逐渐下降,在72h降为2245.3±271.6仍高于假手术组和正常组且有统计学意义(p<0.05);镜下所见模型B组胰腺间质水肿;红细胞漏出;炎细胞浸润。腺泡细胞水肿;点片状出血;灶性变性、坏死;部分导管扩张。病理学评分模型B组与假手术组各时点比较9.89±2.11 vs 1.27±1.13、10.25±1.98 vs 1.32±1.28、11.71±2.11 vs 1.03±0.11、13.85±1.05 vs 1.01±0.19、13.89±0.89 vs 0.98±0.07均有显著性差异。
2.模型组大鼠精神萎靡、竖毛、少动倦卧;治疗组大鼠精神状态较好、活动较多、排便次数增加、肛周污染明显。假手术组无死亡记录,治疗组SAP大鼠死亡率低。模型和治疗组6h、12h、24h、48h的死亡率分别为0%(0/10)、20%(2/10)、40%(4/10)、50%(5/10)和0%(0/10)、20%(2/10)、30%(3/10)、30%(3/10);治疗组24h死亡率低于模型(p<0.05)
3.假手术组淀粉酶在造模后6h一过性升高,随后恢复正常;模型组淀粉酶造模后6h最高,以后随时间逐渐下降,但在48h仍高于假手术组(p<0.05);与模型比较,治疗组造模后12h降低开始有统计学意义(p<0.05),48h与假手术组比较无差异
4.假手术组血清DAO水平在造模前后无变化(p>0.05);治疗组血清DAO水平在造模后24 h和48 h较模型组降低有显著性差异(p<0.05)
5.假手术组术后6h可见胰腺腺泡细胞轻度水肿、无出血及坏死。模型组可见胰腺间质水肿,红细胞漏出,炎细胞浸润,腺泡细胞水肿,点片状出血,灶性变性、坏死,部分胰腺导管扩张,随时间推移胰腺组织病理学评分逐渐加重。治疗组24h以上改变均减轻病理学评分降低有统计学意义。
6.光镜下假手术组肠黏膜绒毛结构完整,上皮呈高柱状,间质无水肿、无中性粒细胞浸润。模型组肠黏膜结构损伤明显,并呈进行性变化,尤以制模24h最明显,可见大鼠回肠间质水肿并有点状出血,血管淋巴管均扩张,还可见大量中性粒细胞浸润伴淋巴滤泡增生,肠绒毛水肿增粗,高度缩短,顶端上皮有片状坏死、脱落,杯状细胞减少,排列紊乱;黏膜厚度变薄,黏膜腺体排列稀疏,腺体减少;中药清胰颗粒治疗组在造模12h时与模型组相比病理损伤有所减轻,表现为炎症细胞浸润减少,绒毛损伤脱落减少,黏膜厚度及绒毛高度均有改善,造模后24 h开始有显著的差异。术后48 h各指标均接近正常值
7.各组小肠黏膜claudin-1均分布于肠上皮紧密连接的细胞膜(包括细胞膜顶部),膜内近侧的胞质区少量染色,为棕黄色染色颗粒,胞核及核膜无表达。假手术Claudin-1蛋白在细胞膜表达且为强阳性;与假手术组比较,模型组claudin-1表达明显下降p<0.05);与模型组比较,治疗组造模后各时间点Claudin-1表达升高且有统计学意义(p<0.05)
结论:
1.应用静脉留置针导管经十二指肠乳头逆行注射3.5%牛磺胆酸钠(0.1ml/100g体重、注射速度为0.15ml/min)诱导的SAP大鼠动物模型是Aho法制备SAP大鼠模型的改良,是进行SAP中药临床研究科研较为理想的动物模型
2.早期应用清胰颗粒能够改善SAP大鼠胰腺组织的损伤,减轻肠黏膜和肠绒毛萎缩,提高肠道紧密连接蛋白Claudin-1水平的表达水平,降低肠黏膜通透性保护肠屏障,降低死亡率。
Objectives:To create the animal model with severe acute pancreatitis which can adapt to scientific research,and to investigate the effects of Qingyi granules on the intestinal mucosa barrier in rats with severe acute pancreatitis(SAP). Methods:Healthy male Wistar rats were divided into normal group,sham operation group and model A,B,C group,Severe acute pancreatitis model was induced by retrograde injection of sodium deoxycholate into the biliopancreatic duct in rats.,the sham operation group and model A,B,C Group rat,respectively,by retrograde injection of saline and 2%,3.5%,5%sodium deoxycholate,observed mortality and the extent of pancreatic injury;then 150 healthy male Wistar rats were randomly divided into 3 groups:sham-operation group,model group and treatment group.The model group and the treatment group were retrograde biliopancreatic injection of 3.5%sodium deoxycholate to create SAP model,and treatment group were given orally Qingyi granules at 2 hours before induction of SAP,at 6h,18h,30h and 42h after SAP,the model group were given placebo in the same way.The levels of serum amylase and diamine oxidase were determined,the histopathology of pancreatic and terminal ileum tissue were examined by hematoxylin and eosin(HE) staining at 0h,6 h、12 h、24 h and 48h after SAP and histologic assessment was performed.At the same time,we measured intestinal villus height,mucosal thickness and detection of small intestinal mucosal tight junction protein Claudin-1 expression by immunohistochemistry.
Results:
1.Sham-operated group was no death records,the mortality of models A,B,C groups after 72h were 20%,50%,70%;the level of amylase in model B group after 6 h up to 9023.0±1924.5 U/L and was a gradual decline over time,after 72 h reduced to 2245.3±271.6 U / L,but still higher than the sham-operated group and the normal group and were statistically significant(p <0.05);In model B group,the pancreas showed that interstitial edema,red blood cell leakage,inflammatory cell infiltration, acinar cells edema,point sheet hemorrhage,focal degeneration and necrosis. Pathology score of model B group and sham-operated group in every time point 9.89±2.11 vs 1.27±1.13,10.25±1.98 vs 1.32±1.28,11.71±2.11 vs 1.03±0.11, 13.85±1.05 vs 1.01±0.19,13.89±0.89 vs0.98±0.07 were showed difference significantly.
2.Model rats showed apathetic,erect hair,lying tired paucimobilis;In treated group rats showed better mental state,activities of large increase in the number of defecation,perianal obvious pollution.Sham-operated group without death records, the mortality of rats with SAP were lower in treatment group.The mortality of rats with SAP in model group and treatment group were 0%(0/10),20%(2/10)、40% (4/10)、50%(5/10) and 0%(0/10)、20%(2/10)、30%(3/10)、30%(3/10) respectively.The mortality of the treatment group in 24 h was lower than the model group(p <0.05).
3.The level of amylase in sham-operated group appeared transient increase after model 6h and then returned to normal;In model group model,the level of amylase was highest after model 6 h,and gradually decreased with time,but in the 48 h was still higher than sham-operated group(p <0.05);Compared with the model group,the level of amylase in treatment group 12 h after began to reduce(p <0.05),in 48 h they showed no differences
4.The level of serum DAO in sham-operated group before and after operation was no change (P> 0.05);The levels of serum DAO in treatment group after 24 h and 48 h was lower than the model group(p <0.05).
5.After model 6h in sham-operated group acinar cells can be seen with mild edema, no bleeding and necrosis.In model group,the pancreas was Observated that interstitial edema,red blood cell leakage,inflammatory cell infiltration,acinar cells,edema, patchy hemorrhage point,focal degeneration and necrosis,and some glandular dilatation,the pathology score of pancreatic tissues gradually increased.The changes with 24 h and more in treatment group was decreasing,which was significance in statistics.
6.Under light microscope,the villi structural integrity of the intestinal mucosa in sham-operated group was showed a high columnar epithelium,interstitial edema,no neutrophil infiltration.In model group,the structure of intestinal mucosa was damaged significantly in a progressive manner,particularly in the most obvious mold 24h,showing interstitial edema in rat ileum and a bit like bleeding,the expansion of lymphatic vessels,but was also showed that a large number of neutrophil infiltration with lymphoid follicular hyperplasia,thickening of intestinal villi edema,high degree of shortening,there was patchy epithelial necrosis of the top,falling,goblet cell decrease with disorder;mucosal thickness were becamed thinner,mucosa with sparse glands,glands reduced;When compared with the model group,the treatment of traditional Chinese medicine Qing Yi granules 12h in the model group reduced the pathological damage,manifested as reduced inflammatory cell infiltration,villous injury to reduce shedding,mucosal thickness and villous height were improved,24h after the beginning of the model with significant differences.48h after the operation, the indicators were close to normal.
7.The claudin-1 of Small intestinal mucosa in each group were distributed in intestinal epithelial tight junction of cell membranes(including the cell membrane at the top),cytoplasmic area of membrane proximal appeared a small amount of staining, with staining brown granules,but nucleus and nuclear membrane without expression. The Claudin-1 protein of sham-operation group expression in the cell membrane and was strongly positive;Compared with the sham-operated group,the expression of claudin-1 was low in model group(p <0.05);Compared with the model group,the Claudin -1 of treatment group at different time points after model expression was higher(p < 0.05)
Conclusion:
1.Application of intravenous catheter system from duodenal catheter by retrograde cholangiopancreatography injection of 3.5%sodium taurocholate to establish SAP model(0.1ml/100g weight,speed of injection 0.15ml/min) is a improved model from preparation Aho SAP method,and is a good research animal model for SAP.
2.Early application of Qingyi granules can improve the damage of pancreatic tissue in rats with SAP,reduce the intestinal mucosa and intestinal villus atrophy,improve intestinal tight junction protein Claudin-1 expression levels,reduce the permeability of intestinal mucosa,and decrease mortality.
引文
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[8]Redha F,Uhlschmid G,Ammann RW,Injection of microspheres into pancreatic arteries causes acute hemorrhagic pancreatitis in the rat:a new animal model.Pancreas.1990 Mar;5(2):188-93.
[9]薛建国,王宇,许元弟.建立大鼠急性出血坏死性胰腺炎模型方法的改进[J].中华实验外科杂志.1994;11(5):313.
[10]Lampel M,Kern HF.Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue[J].Virchows Arch A Pathol Anat Histol,1977,373(2):97-117.
[11]Niederau C,FerrellL D,Grendell JH.Caerulein-induced acute necrotizing pancreatitis in mice:protective effects of proglumide,benzotript,and secretin[J].Gastroenterology,1985,88(5):1192-1204.
[12]孔棣,野村秀明,今野元博.大柴胡汤和前列腺素E对蛙皮素和内毒素引起的大鼠急性胰腺炎的作用[J].中国中西医结合外科杂志,1997,3(5):297-300.
[13]Cosen-Broker L I,Binker M G,Negri G,et al.Acute Pancreatitis Possible Initial Triggering Mechanism and Prophylaxis[J].Pancreatology,2003,3(6):445-456.
[14]倪弘,崔乃强,李继坤.不同程度急性胰腺炎大鼠早期TNF、LPS及酶学的变化[J].中国中西医结合外科杂志,1997,3(2):115-118.
[15]刘长宝,崔乃强,王占国.加昧清胰汤对坏死性胰腺炎细菌移位抑制的实验研究[J].天津中医,2002,19(5):55-57.
[16]Ammorri BJ.Role of the gut in the course of severe acute pancreatitis[J].Pancreas,2003;26(2):122
[17]Furuya T,Soeno T,Komatsu M.Strategy for bacterial translocation in acute pancreatitis[J].Nippon Shokakibyo Gakkai Zasshi,2004;101(5):502
[18]Chiu CJ,McArdle AH,Brown R.Intestinal mucosal lesion in low-flow states.Arch Surg,1970,101(4):478-483]
[19]Swaroop VS,Sruesh T,Jonathan E.Severe acute pancreatitis.JAMA,2004,291:2865-2868
[20]王兴鹏.重视肠道衰竭在重症急性胰腺炎发病中的作用[J].中华消化杂志,2002,22(1):5-6
[21]Yasuda T,Takeyama Y,Ueda T,et al.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatitis.J Surg Res 2006;135:18-26
[22]刘长宝,崔乃强,王占国,等.加味清胰汤对坏死性胰腺炎细菌易位抑制的实验研究[J].天津中医,2002,19(5):55-57.
[23]Rahman SH,Ammori BJ,HolmfieId J,Larvin M,McMahon MJ.Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis[J]..J Gastrointest Surg 2003;7:26-35;discussion 35-36
[24]Yasuda T,Takeyama Y,Ueda T,Shinzeki M,Sawa H,Nakajima T,Kuroda Y.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatitis[J]..J Surg Res 2006;135:18-26
[25]崔乃强,傅强,邱奇等.通里攻下法对SIRS/MODS的治疗价值-多中心临床分析[J].中国中西医结合外科杂志2007;13(1):3-7
[26]Norwood MG,Bown MJ,Lioyd G,et al.The clinical value of the systemic inflammatory response syndrome in abdominal aortic aneurysm repair[J].Eur J Vasc Endovasc Surg,2004,27(3):292-298
[27]Leser HG,,Gross V,Scheibenbogen C,et al.Elevation of serum interleukin-6concentration precedes acute-phase response and reflects severity in acute pancreatitis[J].Gastroenterology,1991,101(3 ):782 -785.
[28]李文星,王锋,韩德五等.重症急性胰腺炎时肠源性内毒素血症与TNF-α、IL-1、NO及MDA之间的相关性研究[J].山西医科大学学报,2006,37(9):911-914.
[29]韩恩昆,吴咸中.大承气汤和活血清胰汤对重型急性胰腺炎肺损伤治疗的实验研究[J].中国中西医结合外科杂志,2004,2:
[30]Surbatovic M,Jovanovic K,Radakovic S,et al.Pathophysiological aspects of severe acute pancreatitis-associated lung injury[J].Srp Arh Celok Lek.2005;133(1-2):76-81
[31]倪弘,崔乃强,吴成中,等.大黄对急性胰腺炎大鼠早期的治疗作用[J].中国中西医结合外科杂志,1997,3(5):314-316.
[32]吕新生,张翼,李宜雄等.甘遂治疗重症急性腺炎[J]..中国普通外科杂志,2004,13(6):401-404
[33]Ryan CM,Atkins MB,Mier JW,et a.l Gutmacromolecular permeability in pancreatitis correlateswith severity ofdisease in rats[J]..Gastroenterology,1993,104:890-895.
[34]Ammori BJ,Leeder PC,King RF,et a.l Early increase in intestinal permeability in patientswith severe acute pancreatitis:correlation with endotoxemia,organ failure,and mortality[J]..J Gastrointest Surg,1999,3:252-26.
[35]Furuse M,Fujita K,Hiiragi T,et al.Claudin-1 and -2:Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin[J].J Cell B iol,1998,141(7):1539 - 1550.
[36]Tursen K,Troy TC.Barriers built on claudins[J].J Cell Sci,2004,117(12):2435-2447.
[1]Ammorri BJ.Role of the gut in the course of severe acute pancreatitis[J].Pancreas,2003;26(2):122
[2]Furuya T,Soeno T,Komatsu M.Strategy for bacterial translocation in acute pancreatitis[J].Nippon Shokakibyo Gakkai Zasshi,2004;101(5):502
[3]Yasuda T,Takeyama Y,Ueda T,et al.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatit-is[J].J Surg Res,2006;135(1):18
[4]Nagpal K,Minocha VR,Agrawal V,et al.Evaluation of intestinal mucosal permeability function in patients with acute pancreatitis[J].Am J Surg,2006;192(1):24
[5]Van Felius ID,Akkermans LM,Bosscha K,et al.Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis[J].Neurogas- troenterol Motil,2003;15(3):267
[6]Ammori BJ,Cairns A,Dixon MF,et al.Altered intestinal morphology and immunity in patients with acute necrotizing pancreatitis[J].Hepatobiliary Pancreat Surg,2002;9(4):490
[7]徐敏,王兴鹏,袁耀宗等.急性胰腺炎患者胃肠动力的变化及其机制研究[J].2002,11(5):327-330.
[8]Gue M,Junien JL,Bueno L.Conditioned emotional response in rats enhances colonic motility through the central release of corticotrophin releasing factor[J].Gastroenterology 1991;100:964-970
[9]王兴鹏,王冰娴,吴凯,等。细胞凋亡在急性坏死性胰腺炎早期肠黏膜上皮细胞死亡中的作用[J].中华消化杂志,2001;21(5):267
[10]Takeyama Y.Significance of apoptotic cell death in systermic complications with severe acute pancreatitis[J].J Gastroenterol,2005;40(1):1
[11]Inoue K,Hirota M,Kimura Y,et al.Further evidence for endothelin as an important mediator of pancreatic and intestinal ischemia in severe acute pancreatitis[J].Pancreas,2003;26(3):218
[12]Li Y,Zhou ZG,Zhang J,et al.Microcirculatory detection of Toll-like receptor 4 in rat pancreas and intestine[J].Clin Hemorheol Microcirc,2006;34(1-2):213
[13]Makhija R,Kingsnorth AN.Cytokine storm in acute pancreatitis[J].Hepatobiliary Pancreat Surg,2002,9(4):401-410.
[14]Leveau P,Wang X,Sun Z,et al.Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant[J].Biochem Pharmacol,2005,69(9):1325-1331.
[15]秦琦瑜,李勇.TNF-α与IL-6在大鼠急性重症胰腺炎并发全身炎性反应综合征中的作用[J]。河北医药,2008,30(2):140-141.
[16]Bhatia M,Brady M,Shokuhi S,et al.Inflammatory mediators in acute pancreatitis[J].J Pathol,2004,190:117-125.
[17]Demols A,Vanlaethem J,Quertinmont E,et al.Endogenous IL-10 modulates fibrosis and regeneration in experimental chronic pancreas- titis[J].AmJ Physiol Gastrointest Liver Physiol,2002,282:1105-1112.
[18]Surbatovic M,Jovanovic K,Radakovic S,et al.Pathophysiological aspects of severe acute pancreatitis-associated lung injury[J].Srp Arh Celok Lek,2005,133:76-81
[19]吕艺,姜小国,曹卫红,等.卡巴胆碱对肠缺血-再灌流动物脏器功能的保护作用[J].中华急诊医学杂志,2006,15(3):228
[20]黎君友,孙丹,吕 艺,等.肠缺血再灌注对小肠屏障、吸收、通透和传输功能的影响[J].世界华人消化杂志,2004,12(2):464
[21]Marik PE,zaloga GP.Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis[J].BMJ,2004,328:1407.
[22]崔乃强,傅强,邱奇等.通里攻下法对SIRS/MODS的治疗价值-多中心临床分析[J].中国中西医结合外科杂志2007;13(1):3-7
[23]马涛,齐清会,简序等.大黄素对大鼠结肠环行平滑肌细胞Ca~(2+)的影响[J].世界华人消化杂志2003;11:1699-1702
[24]张子理,陈蔚文.党参、黄芪、白术、甘草提取部位对小肠上皮细胞增殖的影响[J].中药药理与临床,2002,18(1):10.
[25]刘承哲,刘牧林.大黄对多器官衰竭大鼠肠黏膜屏障的保护作用.蚌埠医学院学报[J],1998,23(6):380.
[26]谢肄聪,唐方.藿香正气软胶囊对肠屏障功能保护作用的机理研究.中国中药杂 志[J],2004,29(5):456.
[27]张仁岭,张胜华,冯寿全.四君子汤加大黄对脓毒症大鼠肠黏膜屏障功能的保护作用[J].中国中西医结合消化杂志,2006,14(3):160.
[28]尤家平,蒋道国,李广元.芪连液保留灌肠治疗婴幼儿秋季腹泻临床与实验研究[J].中国中西医结合杂志,2000,20(9):664.
[29]刘蓉,唐方冲药保护肠屏障功能研究概况[J].上海中医药杂志,2004,38(12):57.
[30]王万铁,徐正,林丽娜,等.川芎嗪对肠黏膜屏障功能的保护作用[J].中国病理生理杂志,2001,17(9):882.
[31]夏中元,罗涛,夏芳,等.生脉注射液对肠黏膜再灌注损伤保护作用机制的实验研究[J].中华麻醉学杂志,2001,21(5):299.
[32]孟德胜,汪仕良.槲皮素等对烫伤后小鼠肠黏膜损伤的保护作用[J].中国药理学通报,2000,16(6):673.
[2]Appelros S,Lindgren S,Borgstrom A.Short and Long Term Outcome of Severe Acute Pancreatitis[J].Ene J Surg,2001,167(4):281-286.
[3]Aho HJ.Experimental pancreatitis in the rats:sodium taurocholate induced acute hemorrhagic pancreatitis.Scand J Gastroenterol.1980;15(4):411-416.
[4]Spormann H,Sckolowski A,Letko,G.Effect of temporary ischemia upon development and histological pattens of acute pancreatitis in the rat.Pathol Res Pract.1989;184:507-513.
[5]Janschmidt David W Rattner,Kent Lewandrowski,et al.A better model of acute pancreatitis for evaluating therapy.Ann Surg.l992;215:44-46.
[6]Nevalainen TJ.Acute pancreatitis caused by closed by closed duodenal loop in the rat[J].Scand J Gasteroent,1975,10(5):521-527.
[7]秦仁义,吴在德.新型的胆源性胰腺炎动物模型.中华实验外科杂志.1998;15(1):70-71.
[8]Redha F,Uhlschmid G,Ammann RW,Injection of microspheres into pancreatic arteries causes acute hemorrhagic pancreatitis in the rat:a new animal model.Pancreas.1990 Mar;5(2):188-93.
[9]薛建国,王宇,许元弟.建立大鼠急性出血坏死性胰腺炎模型方法的改进[J].中华实验外科杂志.1994;11(5):313.
[10]Lampel M,Kern HF.Acute interstitial pancreatitis in the rat induced by excessive doses of a pancreatic secretagogue[J].Virchows Arch A Pathol Anat Histol,1977,373(2):97-117.
[11]Niederau C,FerrellL D,Grendell JH.Caerulein-induced acute necrotizing pancreatitis in mice:protective effects of proglumide,benzotript,and secretin[J].Gastroenterology,1985,88(5):1192-1204.
[12]孔棣,野村秀明,今野元博.大柴胡汤和前列腺素E对蛙皮素和内毒素引起的大鼠急性胰腺炎的作用[J].中国中西医结合外科杂志,1997,3(5):297-300.
[13]Cosen-Broker L I,Binker M G,Negri G,et al.Acute Pancreatitis Possible Initial Triggering Mechanism and Prophylaxis[J].Pancreatology,2003,3(6):445-456.
[14]倪弘,崔乃强,李继坤.不同程度急性胰腺炎大鼠早期TNF、LPS及酶学的变化[J].中国中西医结合外科杂志,1997,3(2):115-118.
[15]刘长宝,崔乃强,王占国.加昧清胰汤对坏死性胰腺炎细菌移位抑制的实验研究[J].天津中医,2002,19(5):55-57.
[16]Ammorri BJ.Role of the gut in the course of severe acute pancreatitis[J].Pancreas,2003;26(2):122
[17]Furuya T,Soeno T,Komatsu M.Strategy for bacterial translocation in acute pancreatitis[J].Nippon Shokakibyo Gakkai Zasshi,2004;101(5):502
[18]Chiu CJ,McArdle AH,Brown R.Intestinal mucosal lesion in low-flow states.Arch Surg,1970,101(4):478-483]
[19]Swaroop VS,Sruesh T,Jonathan E.Severe acute pancreatitis.JAMA,2004,291:2865-2868
[20]王兴鹏.重视肠道衰竭在重症急性胰腺炎发病中的作用[J].中华消化杂志,2002,22(1):5-6
[21]Yasuda T,Takeyama Y,Ueda T,et al.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatitis.J Surg Res 2006;135:18-26
[22]刘长宝,崔乃强,王占国,等.加味清胰汤对坏死性胰腺炎细菌易位抑制的实验研究[J].天津中医,2002,19(5):55-57.
[23]Rahman SH,Ammori BJ,HolmfieId J,Larvin M,McMahon MJ.Intestinal hypoperfusion contributes to gut barrier failure in severe acute pancreatitis[J]..J Gastrointest Surg 2003;7:26-35;discussion 35-36
[24]Yasuda T,Takeyama Y,Ueda T,Shinzeki M,Sawa H,Nakajima T,Kuroda Y.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatitis[J]..J Surg Res 2006;135:18-26
[25]崔乃强,傅强,邱奇等.通里攻下法对SIRS/MODS的治疗价值-多中心临床分析[J].中国中西医结合外科杂志2007;13(1):3-7
[26]Norwood MG,Bown MJ,Lioyd G,et al.The clinical value of the systemic inflammatory response syndrome in abdominal aortic aneurysm repair[J].Eur J Vasc Endovasc Surg,2004,27(3):292-298
[27]Leser HG,,Gross V,Scheibenbogen C,et al.Elevation of serum interleukin-6concentration precedes acute-phase response and reflects severity in acute pancreatitis[J].Gastroenterology,1991,101(3 ):782 -785.
[28]李文星,王锋,韩德五等.重症急性胰腺炎时肠源性内毒素血症与TNF-α、IL-1、NO及MDA之间的相关性研究[J].山西医科大学学报,2006,37(9):911-914.
[29]韩恩昆,吴咸中.大承气汤和活血清胰汤对重型急性胰腺炎肺损伤治疗的实验研究[J].中国中西医结合外科杂志,2004,2:
[30]Surbatovic M,Jovanovic K,Radakovic S,et al.Pathophysiological aspects of severe acute pancreatitis-associated lung injury[J].Srp Arh Celok Lek.2005;133(1-2):76-81
[31]倪弘,崔乃强,吴成中,等.大黄对急性胰腺炎大鼠早期的治疗作用[J].中国中西医结合外科杂志,1997,3(5):314-316.
[32]吕新生,张翼,李宜雄等.甘遂治疗重症急性腺炎[J]..中国普通外科杂志,2004,13(6):401-404
[33]Ryan CM,Atkins MB,Mier JW,et a.l Gutmacromolecular permeability in pancreatitis correlateswith severity ofdisease in rats[J]..Gastroenterology,1993,104:890-895.
[34]Ammori BJ,Leeder PC,King RF,et a.l Early increase in intestinal permeability in patientswith severe acute pancreatitis:correlation with endotoxemia,organ failure,and mortality[J]..J Gastrointest Surg,1999,3:252-26.
[35]Furuse M,Fujita K,Hiiragi T,et al.Claudin-1 and -2:Novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin[J].J Cell B iol,1998,141(7):1539 - 1550.
[36]Tursen K,Troy TC.Barriers built on claudins[J].J Cell Sci,2004,117(12):2435-2447.
[1]Ammorri BJ.Role of the gut in the course of severe acute pancreatitis[J].Pancreas,2003;26(2):122
[2]Furuya T,Soeno T,Komatsu M.Strategy for bacterial translocation in acute pancreatitis[J].Nippon Shokakibyo Gakkai Zasshi,2004;101(5):502
[3]Yasuda T,Takeyama Y,Ueda T,et al.Breakdown of intestinal mucosa via accelerated apoptosis increases intestinal permeability in experimental severe acute pancreatit-is[J].J Surg Res,2006;135(1):18
[4]Nagpal K,Minocha VR,Agrawal V,et al.Evaluation of intestinal mucosal permeability function in patients with acute pancreatitis[J].Am J Surg,2006;192(1):24
[5]Van Felius ID,Akkermans LM,Bosscha K,et al.Interdigestive small bowel motility and duodenal bacterial overgrowth in experimental acute pancreatitis[J].Neurogas- troenterol Motil,2003;15(3):267
[6]Ammori BJ,Cairns A,Dixon MF,et al.Altered intestinal morphology and immunity in patients with acute necrotizing pancreatitis[J].Hepatobiliary Pancreat Surg,2002;9(4):490
[7]徐敏,王兴鹏,袁耀宗等.急性胰腺炎患者胃肠动力的变化及其机制研究[J].2002,11(5):327-330.
[8]Gue M,Junien JL,Bueno L.Conditioned emotional response in rats enhances colonic motility through the central release of corticotrophin releasing factor[J].Gastroenterology 1991;100:964-970
[9]王兴鹏,王冰娴,吴凯,等。细胞凋亡在急性坏死性胰腺炎早期肠黏膜上皮细胞死亡中的作用[J].中华消化杂志,2001;21(5):267
[10]Takeyama Y.Significance of apoptotic cell death in systermic complications with severe acute pancreatitis[J].J Gastroenterol,2005;40(1):1
[11]Inoue K,Hirota M,Kimura Y,et al.Further evidence for endothelin as an important mediator of pancreatic and intestinal ischemia in severe acute pancreatitis[J].Pancreas,2003;26(3):218
[12]Li Y,Zhou ZG,Zhang J,et al.Microcirculatory detection of Toll-like receptor 4 in rat pancreas and intestine[J].Clin Hemorheol Microcirc,2006;34(1-2):213
[13]Makhija R,Kingsnorth AN.Cytokine storm in acute pancreatitis[J].Hepatobiliary Pancreat Surg,2002,9(4):401-410.
[14]Leveau P,Wang X,Sun Z,et al.Severity of pancreatitis-associated gut barrier dysfunction is reduced following treatment with the PAF inhibitor lexipafant[J].Biochem Pharmacol,2005,69(9):1325-1331.
[15]秦琦瑜,李勇.TNF-α与IL-6在大鼠急性重症胰腺炎并发全身炎性反应综合征中的作用[J]。河北医药,2008,30(2):140-141.
[16]Bhatia M,Brady M,Shokuhi S,et al.Inflammatory mediators in acute pancreatitis[J].J Pathol,2004,190:117-125.
[17]Demols A,Vanlaethem J,Quertinmont E,et al.Endogenous IL-10 modulates fibrosis and regeneration in experimental chronic pancreas- titis[J].AmJ Physiol Gastrointest Liver Physiol,2002,282:1105-1112.
[18]Surbatovic M,Jovanovic K,Radakovic S,et al.Pathophysiological aspects of severe acute pancreatitis-associated lung injury[J].Srp Arh Celok Lek,2005,133:76-81
[19]吕艺,姜小国,曹卫红,等.卡巴胆碱对肠缺血-再灌流动物脏器功能的保护作用[J].中华急诊医学杂志,2006,15(3):228
[20]黎君友,孙丹,吕 艺,等.肠缺血再灌注对小肠屏障、吸收、通透和传输功能的影响[J].世界华人消化杂志,2004,12(2):464
[21]Marik PE,zaloga GP.Meta-analysis of parenteral nutrition versus enteral nutrition in patients with acute pancreatitis[J].BMJ,2004,328:1407.
[22]崔乃强,傅强,邱奇等.通里攻下法对SIRS/MODS的治疗价值-多中心临床分析[J].中国中西医结合外科杂志2007;13(1):3-7
[23]马涛,齐清会,简序等.大黄素对大鼠结肠环行平滑肌细胞Ca~(2+)的影响[J].世界华人消化杂志2003;11:1699-1702
[24]张子理,陈蔚文.党参、黄芪、白术、甘草提取部位对小肠上皮细胞增殖的影响[J].中药药理与临床,2002,18(1):10.
[25]刘承哲,刘牧林.大黄对多器官衰竭大鼠肠黏膜屏障的保护作用.蚌埠医学院学报[J],1998,23(6):380.
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