重症急性胰腺炎大鼠肾损伤的病理生理变化
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摘要
目的:重症急性胰腺炎(SAP)是临床上比较常见的急腹症之一,其发病急,病势迅猛,多系统器官功能不全综合症(MODS)发生率高,严重时可发生急性肾功能衰竭(ARF)。本文通过动物实验,人为诱导建立大鼠重症急性胰腺炎模型,在零干预的情况下,动态观察肾脏损伤的各项指标,探讨重症急性胰腺炎不同病程时肾损伤的程度,为临床急性胰腺炎患者的诊断及治疗提供参考。
方法:取健康SD大鼠96只,雌雄不限,体重300～350克,随机分为对照(SO)组和重症急性胰腺炎(SAP)组,每组实验动物48只。实验前12h开始禁食不禁饮,10%水合氯醛(0.3mg/100g)腹腔注射麻醉,开腹,显露胰胆管,阻断近肝门处胆管后,4号头皮针逆行插入胰胆管并固定,将3.5%牛黄胆酸钠按0.1ml/100g以恒速注入胰胆管,常规关腹,皮下注射生理盐水1ml/100g/h,补充血容量。对照组自胰胆管注入等量生理盐水。每组大鼠于模型制备后3h、6h、9h、12h分为四批,每批12只,经尿集笼留取各时间段尿样,-20℃低温保存,以备测定尿中β2微球蛋白含量;动物心脏采血5ml,随即3000r/min离心分离血清,-80℃低温保存,以备测定血清淀粉酶、BUN浓度;手术切除大鼠胰腺,甲醛固定后沿主胰管方向取胰腺组织一块;取左肾,甲醛固定后经肾门取肾组织一块,常规将胰腺、肾脏标本固定、脱水、浸蜡、包埋、切片。HE染色后光镜观察下观察胰腺形态学变化;肾脏标本一组HE染色后光镜观察下对肾损伤进行组织学评分,一组应用免疫组化测定肾组织中Il-1β的表达率。应用统计学方法对所得结果进行数据分析。
结果:
光镜观察下:SO组胰腺及肾脏标本均未见明显病理改变;SAP组:胰腺标本可见不同程度腺泡细胞坏死,间质充血、水肿,炎细胞浸润,间质红细胞渗出;肾脏标本可见肾小球萎缩,肾小管扩张,管壁细胞变形,呈扁平状,刷状缘损伤、脱落,细胞浆空泡形成,肾小管腔内有脱落的坏死组织,有时可见管型或碎片形成,间质内可见出血和炎细胞浸润。且随时间延长,胰腺及肾脏的各种病理表现呈加重趋势。
血淀粉酶浓度、BUN浓度、肾损伤组织学评分、肾组织中Il-1β的表达率、尿中β2微球蛋白含量的各组数据统计分析结果如下:
血淀粉酶浓度:SO组:254.50±76.74;SAP组:4123.08±847.75。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间无显著性差异(P>0.05),SAP组内各时间段:3h、6h、9h间均有显著性差异(P<0.05),9h、12h间无显著性差异(P>0.05)。
血BUN浓度:SO组:7.44±0.68;SAP组:137.98±89.15。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间无显性著差异(P>0.05),SAP组间各时间段间均有显著性差异(P<0.05)。
肾损伤组织学评分:SO组:14.13±8.34;SAP组:121.71±43.01。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间均无显著性差异(P>0.05);SAP组各时间段间均有显著性差异(P<0.05)。
肾组织中Il-1β的表达率:SO组:各时间段均无阳性表达; SAP组:3h组均无阳性表达,6h组有1例阳性表达, 9h组有7例阳性表达,12h组均呈阳性表达。以RXC表进行多个率的比较,SAP组内各时间段间有显著性差异(P<0.05),用确切概率法进一步比较得出:3h组与6h组间无显著性差异(P>0.05),6h、9h、12h间均有显著性差异(P<0.05)。
尿中β2微球蛋白含量:SO组:0.101±0.030;SAP组:0.330±0.097。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间均无显著性差异(P>0.05),SAP组各时间段间均有显著性差异(P<0.05)。
结论:1.重症急性胰腺炎时肾损伤程度随SAP病程延长呈递增趋势;2.血浆BUN浓度对判断SAP时肾损伤程度及预后有重要参考价值. 3. Il-1β在重症急性胰腺炎肾组织中表达显著增加,Il-1β表达增加与SAP肾损伤程度具有密切关系,对于判断SAP肾损伤预后有重要意义;4.尿中β2微球蛋白含量能够较早地反映SAP肾损伤发生和程度。
Objective: Severe acute pancreatitis (SAP) is a kind of common surgical acute abdomen disease, acutely morbility, tendency of disease rapidly, high incidence rate of MODS. SAP induces to acute renal failure (ARF) when it is serious enough. This article factitious induced rat’s SAP by animal experiment. Without any of pretreatments on SAP rats and analyzing the change of amylase (AMY)、BUN in serum,β2 microglobulin in urine and the expression ratio of Il-1βin kidney, we investigate the incidence rate and degree of kidney injury during the evolution process and development of SAP. That is to provide a new theory basement for the clinical diagnosis and therapy of SAP.
Methods: 96 Sprague-Dawley rat of body weight 300～350g were randomly devided into 2 group, Group A was sham operatio group(n=48). Group B was the severe acute pancreatitis group (n=48). All animal were anaesthesiaed by intraperitoneal injecting 10% chloral hydrate﹙0.3ml/100g﹚in preoperative. Group B was opened abdomon by operating and inserted a scalp acupuncture﹙No 4﹚in pancreas biliary ducts, then pumped 3.5% sodium taurocholate (0.1ml/100g) with constant speed. Group A was acted by injecting 0.9% NS in pancreas biliary ducts. All animals were supplied subcutaneously with 0.9% normal sodium﹙1ml/100g/h﹚after induction of pancreatitis. Animal were killed at 3h, 6h, 9h,12h and accordingly divided to 4 batch (each batch number of group A, B n=12). The serum was centrifugal separated from blood and reserved in -80℃. Urine was collected by urine collection cage and reserved in -20℃.The specimen of pancreas and kidney were exairesised anhydrated、waxed、embedded and cutted sheets. The pathology of kidney and pancreas were observed through light microscope after HE stained. We determined the concentration of AMY and BUN in serum andβ2 microglobulin concentration in urine. Kidney injury was judged by the degree of tubular injury. The expression ratio of Il-1βin kidney was detected by immunohistochemistry. The urineβ2-MG concentration was detected by ELISA. All test results were analysised with the SAS 6.12 system by computer.
Results:
Observation by light microscope:Samples of kidney and pancreas have no any of pathology change in group SO. But in group SAP, Acinous cell necrosis、stroma hydropsy、inflammation cells infiltrating、RBC exfiltration could be seen in pancreas specimen, nephric globule atrophia、tubular ectasia、border cells cytomorphosis、striated border trauma and amotic、cytolymph vacuolization could be seen in kidney specimen. In some kidney specimen, we find that decididious tissue and necrosis cells、cast and fragements in nephric tubular; haemorrhage and inflammation cells inflatrating in stroma. These pathology changes aggravates with time prolong.
The concentration of AMY、BUN in serum andβ2 microglobulin in urine、the expression ratio of Il-1βin kidney tissue and the score of kidney injury in each group were analysised as:
The concentration of AMY in serum:Group SO:254.50±76.74;Group SAP:4123.08±847.75;Results analysised by T check discovers:Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h (p<0.05) and it has no statistical significance at 9h、12h(p>0.05).
The concentration of BUN in serum:Group SO:7.44±0.68;Group SAP:137.98±89.15;Results analysised by T check discovers : Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers : data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
The score of kidney injury:Group SO:14.13±8.34;Group SAP:121.71±43.01;Results analysised by T check discovers:Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、 6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
The expression ratio of Il-1βin kidney tissue : The specimen in group SO and group SAP at 3h has no masculine expression; 1 case at 6h and 7 cases at 9h and 12 cases at 12h in group SAP have masculine expression. Results analysised by table R×C discovers : data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05). Results analysised by exact propability discovers : data in group SAP has no statistical significance at 3h、6h (p>0.05) and has statistical significance at 6h、9h、12h (p<0.05).
The concentration ofβ2 microglobulin in urine:Group SO:0.101±0.030;Group SAP:0.330±0.097;Results analysised by T check discovers:group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
Conclusions: 1. Kidney injury ralates to the degree of severe acute pancreatitis. 2. The concentration of BUN in serum has significant meaning in Kidney injury. 3. Il-1βexpression in Kidney tissue closely associated with the digree of Kidney injury in Severe acute pancreatitis, it can be used in judging the results of Kidney injury in Severe acute pancreatitis. 4.The level ofβ2 microglobulin in urine reflects the degree of Kidney injury in Severe acute pancreatitis.
方法:取健康SD大鼠96只,雌雄不限,体重300～350克,随机分为对照(SO)组和重症急性胰腺炎(SAP)组,每组实验动物48只。实验前12h开始禁食不禁饮,10%水合氯醛(0.3mg/100g)腹腔注射麻醉,开腹,显露胰胆管,阻断近肝门处胆管后,4号头皮针逆行插入胰胆管并固定,将3.5%牛黄胆酸钠按0.1ml/100g以恒速注入胰胆管,常规关腹,皮下注射生理盐水1ml/100g/h,补充血容量。对照组自胰胆管注入等量生理盐水。每组大鼠于模型制备后3h、6h、9h、12h分为四批,每批12只,经尿集笼留取各时间段尿样,-20℃低温保存,以备测定尿中β2微球蛋白含量;动物心脏采血5ml,随即3000r/min离心分离血清,-80℃低温保存,以备测定血清淀粉酶、BUN浓度;手术切除大鼠胰腺,甲醛固定后沿主胰管方向取胰腺组织一块;取左肾,甲醛固定后经肾门取肾组织一块,常规将胰腺、肾脏标本固定、脱水、浸蜡、包埋、切片。HE染色后光镜观察下观察胰腺形态学变化;肾脏标本一组HE染色后光镜观察下对肾损伤进行组织学评分,一组应用免疫组化测定肾组织中Il-1β的表达率。应用统计学方法对所得结果进行数据分析。
结果:
光镜观察下:SO组胰腺及肾脏标本均未见明显病理改变;SAP组:胰腺标本可见不同程度腺泡细胞坏死,间质充血、水肿,炎细胞浸润,间质红细胞渗出;肾脏标本可见肾小球萎缩,肾小管扩张,管壁细胞变形,呈扁平状,刷状缘损伤、脱落,细胞浆空泡形成,肾小管腔内有脱落的坏死组织,有时可见管型或碎片形成,间质内可见出血和炎细胞浸润。且随时间延长,胰腺及肾脏的各种病理表现呈加重趋势。
血淀粉酶浓度、BUN浓度、肾损伤组织学评分、肾组织中Il-1β的表达率、尿中β2微球蛋白含量的各组数据统计分析结果如下:
血淀粉酶浓度:SO组:254.50±76.74;SAP组:4123.08±847.75。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间无显著性差异(P>0.05),SAP组内各时间段:3h、6h、9h间均有显著性差异(P<0.05),9h、12h间无显著性差异(P>0.05)。
血BUN浓度:SO组:7.44±0.68;SAP组:137.98±89.15。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间无显性著差异(P>0.05),SAP组间各时间段间均有显著性差异(P<0.05)。
肾损伤组织学评分:SO组:14.13±8.34;SAP组:121.71±43.01。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间均无显著性差异(P>0.05);SAP组各时间段间均有显著性差异(P<0.05)。
肾组织中Il-1β的表达率:SO组:各时间段均无阳性表达; SAP组:3h组均无阳性表达,6h组有1例阳性表达, 9h组有7例阳性表达,12h组均呈阳性表达。以RXC表进行多个率的比较,SAP组内各时间段间有显著性差异(P<0.05),用确切概率法进一步比较得出:3h组与6h组间无显著性差异(P>0.05),6h、9h、12h间均有显著性差异(P<0.05)。
尿中β2微球蛋白含量:SO组:0.101±0.030;SAP组:0.330±0.097。以T检验所有数据结果:P<0.05,两组总体均数间差别有显著意义。进一步应用方差分析作各组内比较得出:SO组各时间段间均无显著性差异(P>0.05),SAP组各时间段间均有显著性差异(P<0.05)。
结论:1.重症急性胰腺炎时肾损伤程度随SAP病程延长呈递增趋势;2.血浆BUN浓度对判断SAP时肾损伤程度及预后有重要参考价值. 3. Il-1β在重症急性胰腺炎肾组织中表达显著增加,Il-1β表达增加与SAP肾损伤程度具有密切关系,对于判断SAP肾损伤预后有重要意义;4.尿中β2微球蛋白含量能够较早地反映SAP肾损伤发生和程度。
Objective: Severe acute pancreatitis (SAP) is a kind of common surgical acute abdomen disease, acutely morbility, tendency of disease rapidly, high incidence rate of MODS. SAP induces to acute renal failure (ARF) when it is serious enough. This article factitious induced rat’s SAP by animal experiment. Without any of pretreatments on SAP rats and analyzing the change of amylase (AMY)、BUN in serum,β2 microglobulin in urine and the expression ratio of Il-1βin kidney, we investigate the incidence rate and degree of kidney injury during the evolution process and development of SAP. That is to provide a new theory basement for the clinical diagnosis and therapy of SAP.
Methods: 96 Sprague-Dawley rat of body weight 300～350g were randomly devided into 2 group, Group A was sham operatio group(n=48). Group B was the severe acute pancreatitis group (n=48). All animal were anaesthesiaed by intraperitoneal injecting 10% chloral hydrate﹙0.3ml/100g﹚in preoperative. Group B was opened abdomon by operating and inserted a scalp acupuncture﹙No 4﹚in pancreas biliary ducts, then pumped 3.5% sodium taurocholate (0.1ml/100g) with constant speed. Group A was acted by injecting 0.9% NS in pancreas biliary ducts. All animals were supplied subcutaneously with 0.9% normal sodium﹙1ml/100g/h﹚after induction of pancreatitis. Animal were killed at 3h, 6h, 9h,12h and accordingly divided to 4 batch (each batch number of group A, B n=12). The serum was centrifugal separated from blood and reserved in -80℃. Urine was collected by urine collection cage and reserved in -20℃.The specimen of pancreas and kidney were exairesised anhydrated、waxed、embedded and cutted sheets. The pathology of kidney and pancreas were observed through light microscope after HE stained. We determined the concentration of AMY and BUN in serum andβ2 microglobulin concentration in urine. Kidney injury was judged by the degree of tubular injury. The expression ratio of Il-1βin kidney was detected by immunohistochemistry. The urineβ2-MG concentration was detected by ELISA. All test results were analysised with the SAS 6.12 system by computer.
Results:
Observation by light microscope:Samples of kidney and pancreas have no any of pathology change in group SO. But in group SAP, Acinous cell necrosis、stroma hydropsy、inflammation cells infiltrating、RBC exfiltration could be seen in pancreas specimen, nephric globule atrophia、tubular ectasia、border cells cytomorphosis、striated border trauma and amotic、cytolymph vacuolization could be seen in kidney specimen. In some kidney specimen, we find that decididious tissue and necrosis cells、cast and fragements in nephric tubular; haemorrhage and inflammation cells inflatrating in stroma. These pathology changes aggravates with time prolong.
The concentration of AMY、BUN in serum andβ2 microglobulin in urine、the expression ratio of Il-1βin kidney tissue and the score of kidney injury in each group were analysised as:
The concentration of AMY in serum:Group SO:254.50±76.74;Group SAP:4123.08±847.75;Results analysised by T check discovers:Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h (p<0.05) and it has no statistical significance at 9h、12h(p>0.05).
The concentration of BUN in serum:Group SO:7.44±0.68;Group SAP:137.98±89.15;Results analysised by T check discovers : Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers : data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
The score of kidney injury:Group SO:14.13±8.34;Group SAP:121.71±43.01;Results analysised by T check discovers:Group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、 6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
The expression ratio of Il-1βin kidney tissue : The specimen in group SO and group SAP at 3h has no masculine expression; 1 case at 6h and 7 cases at 9h and 12 cases at 12h in group SAP have masculine expression. Results analysised by table R×C discovers : data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05). Results analysised by exact propability discovers : data in group SAP has no statistical significance at 3h、6h (p>0.05) and has statistical significance at 6h、9h、12h (p<0.05).
The concentration ofβ2 microglobulin in urine:Group SO:0.101±0.030;Group SAP:0.330±0.097;Results analysised by T check discovers:group SO and group SAP were of statistical significance (p<0.05). Results analysised by ANOVA and S-N-K check discovers:data in group SO has no statistical significance at 3h、6h、9h、12h (p>0.05); data in group SAP has statistical significance at 3h、6h、9h、12h (p<0.05).
Conclusions: 1. Kidney injury ralates to the degree of severe acute pancreatitis. 2. The concentration of BUN in serum has significant meaning in Kidney injury. 3. Il-1βexpression in Kidney tissue closely associated with the digree of Kidney injury in Severe acute pancreatitis, it can be used in judging the results of Kidney injury in Severe acute pancreatitis. 4.The level ofβ2 microglobulin in urine reflects the degree of Kidney injury in Severe acute pancreatitis.
引文
1 Pitchumini CS,Agarwal N,Jain. Systemic complication of acute pancreatitis. AM J Gastrienterol,1998,83(6):597～606
2 王雪梅,郑德权,刘玉兰.急性胰腺炎合并肾脏损伤的临床分析.医师进修杂志,2002,25(12):14～16
3 袁耀宗.胰腺病病学新进展与新技术.上海:上海科学技术文献出版社,2001,284
4 姜九华,丁建仁.血、尿 β2MG、尿 Alb 测定对高血压早期肾损害的诊断意义.临床医学,1997,17(12):50
5 NJ Rothwell. Cytokines–killers in the brain. J Physiol, 1999, 514(1):3～17
6 Simon C, Pellicer A, Polan ML. Interleukin–1 system crosstalk between embryo and endometrium in implantation. Human Report, 1995,10(suppl 2):43～54
7 Lanny J, Rosenwasser MD, Denver Colo. Biologic actives of IL-1 and its role in human disease. J Allergy Clin Immunol, 1998,102(3):344～350
8 Lisa RL. Molecular bioligy of ahermoregulation invited reviw:cytokine regulation of fever:studies using gene knockout mice. J Appl Physiol, 2002, 92(6):2648～2655
9 Had M, Norman J, Saba SR. et al Role of IL-1 in ische mic reperfusion injury. J Am Sol Nephrol, 1998, 9(4):614～619
10 Furuichi K, Wada T, Twata Y. et al Administration of FR16753, a new anti–inflammatory compound, prevent renal ische mia/reperfusion injury in mice. Nephrod Dial Transplant, 2002, 17(13):399～407
11 Leonard MO, Hannan K, Burne MJ. et al 15-Epi-16-(fluorophenoxy)-lipoxinA(4)-methyl-methyl-ester, synthetic analogue of 15-epi-lipoxinA(4), is a protective in experimental acute ischemic renal failure. J Am Sol Nephrol, 2002, 13(6):1657～1662
12 龚时文,艾中立,周亚魁.大鼠急性坏死性胰腺炎合并肾损害 及 前 列 腺 素 的 保 护 作 用 . 中 华 消 化 杂志,1995,15(12):82～84
13 Kozolowi S, Takeshim T, Bochncke WH. et al Excess beta 2-microglobulin promoting functional peptide association with purified soluble class 1 MHC molecules. Nature, 1991, 349(6304):74～77
14 Otten GR, Bikoff E, Ribaudo RK. et al Peptide and beta
2-microglobulin regulation of cell surface MHC class I conformation and expression. Immunol, 1992,148:3723～3732
15 Shields MJ, Assefi N, Hodgson W. et al Characterization of the interactions between MHC class 1 subunits:a systematic approach for the engineering of higher affinity variants of beta 2-microglobulin. J Immunol, 1998, 160:2297～2307
16 Shields MJ, Kubota R, Hodgson W. et al The effect of human beta 2-microglobulin on major histocompatibility complex 1 peptide loading and the engineering of a hifh affinity variant. Implications for peptide–basedvaccines. J Biol Chem,1998,273:28010～28018
17 Tysoe-Calnon VA, Grundy JE, Perkins SJ. Molecular comparisons of the beta 2-microglobulin-binding site in class 1 major-histocom patibility-complex a-chains and proteins of related sequences. Biochem J,1991,277(Pt 2):359～369
18 王云帆,陈瑞芬.急性胰腺炎肾脏损害的发生机制.首都医科大学学报,2004,25(2):276
19 Triebling AT, Dlugisz J, Brzozowski J. et al The renal lysisimes in acute experimental pancreatitis in dogs treated with prostacyclin(PG12).Pathol Res Pract,1984 Jan,178:280
20 王妮英,张庆怡.急性胰腺炎的肾损害.国外医学·内科学分册,1996,23(1):24～26
21 陈晓琴,周力,谭玉杰.尿 NAG 测定对诊断胰腺炎早期肾损害的意义.贵阳医学院学报,2002,27(1):47～48
22 孙艺,杨玉荣,周希静.尿 NAG 活性及尿β2MG 水平测定对SLE 患 者 近 端 肾 小 管 变 化 的 探 讨 . 中 华 肾 脏 病 杂志,1995,11:161
23 Peter NM,Gluian L,Murray M. et al A study of urinary NAG and β2-MG excretion. Arthritis and Rheumatism, 1990, 33:1560
24 侯振江,张宗英. β2 微球蛋白测定的临床应用.新医学,1993,2450～55
1 Tennes S, Banks PA. Acute pancreatitis: nonsurgical management. World J Surg, 1997, 21:143
2 Beaux AC, Goldie AS, Ross JA. Serum concentration of imflamatory mediators related to organ failure in patientswith acute pancreatitis. Br J Surg, 1996, 83:346～359
3 Banks RB, Erans SW, Alexander D. et al Is fatal acutepancreatitis a consequence of excessive leukocyte st-mulation?The role of tumor necrosis factor. Cytokine, 1991, 3:12～16
4 Kingnorth A. Role of cytokines and their inhibitorsin acute pancreatitis. Gut, 1997, 40:1～4
5 Pitchumoni CS, Agarwa LN, Jain NK.Systimic complication of acute pancreatitis. Am J Gastroenterol, 1998, 83:597～606
6 Rinderknecht H. Faltal pancreatitis, a consequence of excessive leukocyte stimulation. Int J Pancreatol, 1998, 3:105～112
7 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
8 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
9 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
10 Werner J, Z'graggen K, Warshaw AL. et al Specific pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg.1999 Jun; 229(6): 834-40
11 Panes J,Granger DN.Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinaldisease.Gastroenterology, 1998 May, 114(5): 1066～1090
12 BevilacquaMP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol, 1993,11: 767～804
13 Frossard JL, Saluja A, Bhagat L. The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis associated lung injury. Gastroenterology, 1999 Mar, 116 (3): 694～701
14 Fink G, Yang J, Carter G. et al Acute pancreatitis induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism. J Surg Res, 1997 Jan, 67(1): 94～97
15 Poch B, Gansauge F, Rau B. The role of polymorphonuclear leukocytes and oxygen-derived free radicals in experimental acute pancreatitis: mediators of local destruction and activators of inflammation. FEBS Lett,1999 Nov 19, 461(3): 268～272
16 Hansbrough JF, Wikstrom T, Braide M. et al Neutrophil activation and tissue neutrophil sequestratio in a rat model of thermal injury. J Surg Res, 1996 Feb 15, 61(1): 17～22
17 Greestain RJ, Krakoff LR, Feltouk. Activation of the renin systen in acute pancreatitis. AMJ Med,1987,82:401～404
18 Schmidt 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
19 Mariano F, Guida G, Donati D. et al Production of platelet-activating factor in patients with sepsis-associated acute renel failure. Nephrol Dial Transplant,1999,14(5):1150～1157
20 Yanagisawa M, Kurihara H, Kimura S. et al A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 1988 Mar 31, 332(6163): 411～415
21 Liu XH, Nakano I, Yamaguchi H. et al Protective effect of reactive nitrix oxcide on development of acute pancreatitis in rats. Dig Dis Sci, 1995 40:2162～2169
22 Liaudet L, Soriano FG, Szabo C. Biology of nitric oxide signaling. Crit Care Med, 2000 Apr, 28(4 Suppl): N37～52
23 Girotti AW. Lipid hydroperoxide generatio, turnover, and effector action in biological systems. J Lipid Res, 1998 Aug, 39(8): 1529～1542
24 Chung HT, Pae HO, Choi BM. Et al Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Commun, 2001 Apr 20, 282(5): 1075～1079
25 Haslett C. Granulocyte apoptosis and inflammatory disease. Br Med Bull, 1997, 53(3): 669～683
26 Chen X, Ji B, Han B. et al NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response. Gastroenterology, 2002 Feb, 122(2): 448～457
27 Modolell M, Corraliza IM, Link F. et al Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol, 1995 Apr, 25(4):1101～1104
28 Satoh A, Shimosegawa T, Kimura K. et al Nitric oxide is overproduced by peritoneal macrophages in rat taurocholate pancreatitis: the mechanism of inducible nitric oxide synthase expression. Pancreas, 1998 Nov, 17(4): 402～411
29 Denham 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
30 Wink 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
31 Norman JG, Fink G, Franz M. et al Active interleukin-1 receptor required for maximal progression of acute pancreatitis. Ann Surg, 1996 Feb,223(2): 163～169
32 Formela 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
33 Maruo N, Morita I, Ishizaki. et al Inhibitory effect of interleukin-6 on prostaglandinI 2 production in cultured bovine vascular endothelial cell. Archives Biochem Biophys, 1992, 292:600～604
34 Manabe T, Hirano T, Tobe T. Effect of prostaglandin E2 on cellular, lysosomal and mitochondrial fragility in caerulein-induced pancreatitis rats. Hepatogastroenterology,1993 Oct, 40(5): 463～466
35 Biffl WL, Moore EE, Peterson VM. Interleukin-6 In the injured patient marker of injury or mediator of inflammation? Ann Surg, 1996 Nov, 224(5): 647～649
36 Inagaki T, Hoshino M. Interieukin is a useful marker for early prediction the severity of acute pancreatitis. J Pancrease, 1997, 14(2):1～8
37 Chen CC , Wand SS , Iee FY. et al Proinflammatory cytokinein early assement of prognosis of acute pancreatitis. Am J Gastorenterol, 1999, 94:213～218
38 Jaffray C, Yang J, Carter G. et al Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome. Surgery, 2000 Aug, 128 (2): 225～231
39 Eyndhoven WG, Gamper CJ, Cho E. et al TRAF-3 mRNA splice-deletion variants encode isoforms that induce NF-kappaB activation. Mol Immunol, 1999 Jul, 36(10): 647～658
40 Satoh 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 王雪梅,郑德权,刘玉兰.急性胰腺炎合并肾脏损伤的临床分析.医师进修杂志,2002,25(12):14～16
3 袁耀宗.胰腺病病学新进展与新技术.上海:上海科学技术文献出版社,2001,284
4 姜九华,丁建仁.血、尿 β2MG、尿 Alb 测定对高血压早期肾损害的诊断意义.临床医学,1997,17(12):50
5 NJ Rothwell. Cytokines–killers in the brain. J Physiol, 1999, 514(1):3～17
6 Simon C, Pellicer A, Polan ML. Interleukin–1 system crosstalk between embryo and endometrium in implantation. Human Report, 1995,10(suppl 2):43～54
7 Lanny J, Rosenwasser MD, Denver Colo. Biologic actives of IL-1 and its role in human disease. J Allergy Clin Immunol, 1998,102(3):344～350
8 Lisa RL. Molecular bioligy of ahermoregulation invited reviw:cytokine regulation of fever:studies using gene knockout mice. J Appl Physiol, 2002, 92(6):2648～2655
9 Had M, Norman J, Saba SR. et al Role of IL-1 in ische mic reperfusion injury. J Am Sol Nephrol, 1998, 9(4):614～619
10 Furuichi K, Wada T, Twata Y. et al Administration of FR16753, a new anti–inflammatory compound, prevent renal ische mia/reperfusion injury in mice. Nephrod Dial Transplant, 2002, 17(13):399～407
11 Leonard MO, Hannan K, Burne MJ. et al 15-Epi-16-(fluorophenoxy)-lipoxinA(4)-methyl-methyl-ester, synthetic analogue of 15-epi-lipoxinA(4), is a protective in experimental acute ischemic renal failure. J Am Sol Nephrol, 2002, 13(6):1657～1662
12 龚时文,艾中立,周亚魁.大鼠急性坏死性胰腺炎合并肾损害 及 前 列 腺 素 的 保 护 作 用 . 中 华 消 化 杂志,1995,15(12):82～84
13 Kozolowi S, Takeshim T, Bochncke WH. et al Excess beta 2-microglobulin promoting functional peptide association with purified soluble class 1 MHC molecules. Nature, 1991, 349(6304):74～77
14 Otten GR, Bikoff E, Ribaudo RK. et al Peptide and beta
2-microglobulin regulation of cell surface MHC class I conformation and expression. Immunol, 1992,148:3723～3732
15 Shields MJ, Assefi N, Hodgson W. et al Characterization of the interactions between MHC class 1 subunits:a systematic approach for the engineering of higher affinity variants of beta 2-microglobulin. J Immunol, 1998, 160:2297～2307
16 Shields MJ, Kubota R, Hodgson W. et al The effect of human beta 2-microglobulin on major histocompatibility complex 1 peptide loading and the engineering of a hifh affinity variant. Implications for peptide–basedvaccines. J Biol Chem,1998,273:28010～28018
17 Tysoe-Calnon VA, Grundy JE, Perkins SJ. Molecular comparisons of the beta 2-microglobulin-binding site in class 1 major-histocom patibility-complex a-chains and proteins of related sequences. Biochem J,1991,277(Pt 2):359～369
18 王云帆,陈瑞芬.急性胰腺炎肾脏损害的发生机制.首都医科大学学报,2004,25(2):276
19 Triebling AT, Dlugisz J, Brzozowski J. et al The renal lysisimes in acute experimental pancreatitis in dogs treated with prostacyclin(PG12).Pathol Res Pract,1984 Jan,178:280
20 王妮英,张庆怡.急性胰腺炎的肾损害.国外医学·内科学分册,1996,23(1):24～26
21 陈晓琴,周力,谭玉杰.尿 NAG 测定对诊断胰腺炎早期肾损害的意义.贵阳医学院学报,2002,27(1):47～48
22 孙艺,杨玉荣,周希静.尿 NAG 活性及尿β2MG 水平测定对SLE 患 者 近 端 肾 小 管 变 化 的 探 讨 . 中 华 肾 脏 病 杂志,1995,11:161
23 Peter NM,Gluian L,Murray M. et al A study of urinary NAG and β2-MG excretion. Arthritis and Rheumatism, 1990, 33:1560
24 侯振江,张宗英. β2 微球蛋白测定的临床应用.新医学,1993,2450～55
1 Tennes S, Banks PA. Acute pancreatitis: nonsurgical management. World J Surg, 1997, 21:143
2 Beaux AC, Goldie AS, Ross JA. Serum concentration of imflamatory mediators related to organ failure in patientswith acute pancreatitis. Br J Surg, 1996, 83:346～359
3 Banks RB, Erans SW, Alexander D. et al Is fatal acutepancreatitis a consequence of excessive leukocyte st-mulation?The role of tumor necrosis factor. Cytokine, 1991, 3:12～16
4 Kingnorth A. Role of cytokines and their inhibitorsin acute pancreatitis. Gut, 1997, 40:1～4
5 Pitchumoni CS, Agarwa LN, Jain NK.Systimic complication of acute pancreatitis. Am J Gastroenterol, 1998, 83:597～606
6 Rinderknecht H. Faltal pancreatitis, a consequence of excessive leukocyte stimulation. Int J Pancreatol, 1998, 3:105～112
7 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
8 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
9 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
10 Werner J, Z'graggen K, Warshaw AL. et al Specific pancreatitis with monoclonal antibodies against ICAM-1. Ann Surg.1999 Jun; 229(6): 834-40
11 Panes J,Granger DN.Leukocyte-endothelial cell interactions: molecular mechanisms and implications in gastrointestinaldisease.Gastroenterology, 1998 May, 114(5): 1066～1090
12 BevilacquaMP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol, 1993,11: 767～804
13 Frossard JL, Saluja A, Bhagat L. The role of intercellular adhesion molecule 1 and neutrophils in acute pancreatitis and pancreatitis associated lung injury. Gastroenterology, 1999 Mar, 116 (3): 694～701
14 Fink G, Yang J, Carter G. et al Acute pancreatitis induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism. J Surg Res, 1997 Jan, 67(1): 94～97
15 Poch B, Gansauge F, Rau B. The role of polymorphonuclear leukocytes and oxygen-derived free radicals in experimental acute pancreatitis: mediators of local destruction and activators of inflammation. FEBS Lett,1999 Nov 19, 461(3): 268～272
16 Hansbrough JF, Wikstrom T, Braide M. et al Neutrophil activation and tissue neutrophil sequestratio in a rat model of thermal injury. J Surg Res, 1996 Feb 15, 61(1): 17～22
17 Greestain RJ, Krakoff LR, Feltouk. Activation of the renin systen in acute pancreatitis. AMJ Med,1987,82:401～404
18 Schmidt 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
19 Mariano F, Guida G, Donati D. et al Production of platelet-activating factor in patients with sepsis-associated acute renel failure. Nephrol Dial Transplant,1999,14(5):1150～1157
20 Yanagisawa M, Kurihara H, Kimura S. et al A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature, 1988 Mar 31, 332(6163): 411～415
21 Liu XH, Nakano I, Yamaguchi H. et al Protective effect of reactive nitrix oxcide on development of acute pancreatitis in rats. Dig Dis Sci, 1995 40:2162～2169
22 Liaudet L, Soriano FG, Szabo C. Biology of nitric oxide signaling. Crit Care Med, 2000 Apr, 28(4 Suppl): N37～52
23 Girotti AW. Lipid hydroperoxide generatio, turnover, and effector action in biological systems. J Lipid Res, 1998 Aug, 39(8): 1529～1542
24 Chung HT, Pae HO, Choi BM. Et al Nitric oxide as a bioregulator of apoptosis. Biochem Biophys Res Commun, 2001 Apr 20, 282(5): 1075～1079
25 Haslett C. Granulocyte apoptosis and inflammatory disease. Br Med Bull, 1997, 53(3): 669～683
26 Chen X, Ji B, Han B. et al NF-kappaB activation in pancreas induces pancreatic and systemic inflammatory response. Gastroenterology, 2002 Feb, 122(2): 448～457
27 Modolell M, Corraliza IM, Link F. et al Reciprocal regulation of the nitric oxide synthase/arginase balance in mouse bone marrow-derived macrophages by TH1 and TH2 cytokines. Eur J Immunol, 1995 Apr, 25(4):1101～1104
28 Satoh A, Shimosegawa T, Kimura K. et al Nitric oxide is overproduced by peritoneal macrophages in rat taurocholate pancreatitis: the mechanism of inducible nitric oxide synthase expression. Pancreas, 1998 Nov, 17(4): 402～411
29 Denham 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
30 Wink 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
31 Norman JG, Fink G, Franz M. et al Active interleukin-1 receptor required for maximal progression of acute pancreatitis. Ann Surg, 1996 Feb,223(2): 163～169
32 Formela 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
33 Maruo N, Morita I, Ishizaki. et al Inhibitory effect of interleukin-6 on prostaglandinI 2 production in cultured bovine vascular endothelial cell. Archives Biochem Biophys, 1992, 292:600～604
34 Manabe T, Hirano T, Tobe T. Effect of prostaglandin E2 on cellular, lysosomal and mitochondrial fragility in caerulein-induced pancreatitis rats. Hepatogastroenterology,1993 Oct, 40(5): 463～466
35 Biffl WL, Moore EE, Peterson VM. Interleukin-6 In the injured patient marker of injury or mediator of inflammation? Ann Surg, 1996 Nov, 224(5): 647～649
36 Inagaki T, Hoshino M. Interieukin is a useful marker for early prediction the severity of acute pancreatitis. J Pancrease, 1997, 14(2):1～8
37 Chen CC , Wand SS , Iee FY. et al Proinflammatory cytokinein early assement of prognosis of acute pancreatitis. Am J Gastorenterol, 1999, 94:213～218
38 Jaffray C, Yang J, Carter G. et al Pancreatic elastase activates pulmonary nuclear factor kappa B and inhibitory kappa B, mimicking pancreatitis-associated adult respiratory distress syndrome. Surgery, 2000 Aug, 128 (2): 225～231
39 Eyndhoven WG, Gamper CJ, Cho E. et al TRAF-3 mRNA splice-deletion variants encode isoforms that induce NF-kappaB activation. Mol Immunol, 1999 Jul, 36(10): 647～658
40 Satoh 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