胆道梗阻及再通术后LFA-1表达变化的实验研究
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摘要
目的：初步研究SD大鼠胆道梗阻及再通术后外周血白细胞及肝脏和小肠组织中淋巴细胞功能相关抗原-1(LFA-1)的表达变化。探讨大鼠LFA-1的异常表达与梗阻性黄疸器官功能损伤间的关系。
方法：采用成年SD大鼠120只,随机分为三组,分别建立假手术(SH,n=40)、梗阻性黄疸(OJ,n=40)、胆汁内引流术(ID,n=40)模型。第一次手术OJ组及ID组建立梗阻性黄疸模型,SH组仅分离胆总管；饲养7天后,第二次手术ID组建立胆汁内引流模型,而SH及OJ组仅分离胆总管。于第一次术后7天及第二次术后第1,3,7天留取血液标本及肝脏、末端回肠组织标本。检测比较各组动物血清总胆红素(TB)、白蛋白(ALB)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)水平及肝、末端回肠的病理学变化。利用流式细胞(FCM)方法测定各组LFA-1在静脉血白细胞、肝脏及末端回肠组织中的表达水平,并采用SABC免疫组化方法测定肝脏及末端回肠组织LFA-1的表达情况。
结果：成功建立了三组大鼠动物模型。在胆总管结扎术后第7天时,血清胆红素浓度为213.3+16.8μmol/L,第二次术后第1、3、7天时,ID组血清胆红素持续下降(ID vs SH, P<0.05),而OJ组保持高水平。ALT等酶学指标也呈相同变化。SH组肝脏病理检查显示正常肝小叶结构。胆总管结扎后7天的汇管区、小叶周边可见新生小胆管样上皮细胞,少量炎性细胞浸润；原有肝内胆管上皮细胞有少量脱落现象及少量肝细胞的坏死灶。OJ组二次开腹7天时,胆管上皮细胞增生范围增大,细胞扁平,管腔宽大,其外周基底膜及胶原纤维层增厚。ID组胆肠吻合术后7天时可见肝细胞增生,肝小叶结构逐渐恢复正常,汇管区无明显炎细胞浸润,仍可见纤维组织增生。梗阻性黄疸第7天时,大鼠血液白细胞LFA-1水平(86.97+5.52%)明显高于SH组(35.12±5.37%)(OJ vs SH, P<0.05);第二次术后第7天时,ID组白细胞LFA-1表达水平持续下降(IDvsSH, P>0.05),而OJ组保持高水平。肝脏及末端回肠组织亦有相似的结果。胆总管结扎后第7天肝脏及末端回肠免疫组化LFA-1的表达强度增加,ID组胆肠吻合术后逐渐下降,于术后第7天降至正常,与SH组比较无明显差异(IDvsSH,P>0.05)。
结论：大鼠肝脏阻塞早期即发生明显的损害,机体可产生一定的代偿以改善肝功能,但持续存在的胆管阻塞最终导致肝纤维化。大鼠阻塞性黄疸期内病理形态学的改变显示其肝功能测定值并不能反映其肝脏组织的实际损害程度。LFA-1的表达水平和梗阻性黄疸的发生、发展有显著相关性。胆道梗阻后LFA-1高水平表达,与肝功能及肝脏细胞结构损伤呈一致性,我们认为LFA-1可能在梗阻性黄疸病理生理中起到了重要作用。内引流解除术后可使肝脏及回肠病理形态基本恢复,LFA-1的表达下调。
Objective:To investigate the changes of the expression of Lymphocyte functional antigen-1 (LFA-1) in WBC, liver, distal ileum of obstructive jaundice post-released in SD rats. And to assess relationship between the increased LFA-1 expression and obstructive jaundice.
Methods:One hundred and twenty adult Sprague-Dawley rats were randomly assigned to three groups:sham operation(SH, n=40),obstructive jaundice(OJ, n=40), internal biliary drainage (ID, n=40). OJ was stablished by first operation; After seven days, ID was built by second operation. On the 7th after the first operation and 1st,3 th,7th days after the second operation, the three groups were succumbed and the specimens of blood and liver, distal ileum were collected. The level of total bilirubin(TB), albumin (ALB), alanine transminase (ALT), aspartate aminotransferase (AST) in serum and liver, distal ileum tissue to value the result of the operation.The expression of LAF-1 on WBC, liver, distal ileum tissue at different time points was detected by flow cytometry(FCM). And the LFA-1 expression of liver, distal ileum tissue was determined by SABC(Streptavidin Biotin Peroxidase complex technique) immunohistochemistry method.
Results:Rat models were successfully established. The level of total bilirubin on the 7th day after the ligation was 213.3±16.8μmol/L. On 1st,3th,7th days after the second operation, the level of total bilirubin descended(ID vs SH, P<0.05) in ID rats, but kept higher level in OJ rats. There was a similar change in the biochemical indices such as ALT. The structure of Hepatic Lobules of the SH group was normal. On 7th day after bile duct ligation, new small biliary epithelia cells appeared in the portal areas and around the liver lobulars with some inflammatory cells infiltrated; As epithelial cells of intra-hepatic bile duct exfoliated, some necrosis focuses of hepatic cells were being seen. On 7th day after the second operation, in OJ group, the hyper-plastic areas of intra-hepatic bile duct epithelial cells enlarged, the cells were flat and the lumens of the bile ducts were wide, the basal membrane and collagen fibers layers thickened. On 7th day after the second operation, in ID group, showed hyperplasia in hepatocyte, hepatic lobules gradually returned to normal, and portal area without significant inflammatory cell infiltration. But proliferation of fibrous tissue was still visible.On 7th day after bile duct ligation, the lever of LFA-1 in WBC was significantly elevated(86.97±5.52%)compared with that in SH rats (35.12±5.37%) (OJ vs SH, P<0.05).On 7th day after the second operation, the level of LFA-1 expression descended (ID vs SH, P>0.05) in ID rats, but it kept higher level in OJ rats. There was a similar change in liver and distal ileum. On 7th day after bile duct ligation, the liver and distal ileum showed the increased LFA-1 expression in OJ (OJ vs SH, P<0.05); After the second operation, the level of LFA-1 expression declined gradually, on 7th day, there were no difference between ID and SH(P>0.05).
Conclusion:There is obvious impairment in the early phase of obstructive jaundice; the liver function may be improved to a certain degree by a compensation mechanism; however, the persistence of obstructive jaundice finally leads to hepatic fibrosis. The liver function indicated by the pathomorphology changes can not reflect the actual impairment of liver tissue in obstructive jaundice rats. Increased LFA-1 expression might be related to occurrence and development of rejection. The liver dysfunction and destruction may be mediated by the consequences of LFA-1 binding. Internal drainage could relieve the expression of LFA-1.
方法：采用成年SD大鼠120只,随机分为三组,分别建立假手术(SH,n=40)、梗阻性黄疸(OJ,n=40)、胆汁内引流术(ID,n=40)模型。第一次手术OJ组及ID组建立梗阻性黄疸模型,SH组仅分离胆总管；饲养7天后,第二次手术ID组建立胆汁内引流模型,而SH及OJ组仅分离胆总管。于第一次术后7天及第二次术后第1,3,7天留取血液标本及肝脏、末端回肠组织标本。检测比较各组动物血清总胆红素(TB)、白蛋白(ALB)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)水平及肝、末端回肠的病理学变化。利用流式细胞(FCM)方法测定各组LFA-1在静脉血白细胞、肝脏及末端回肠组织中的表达水平,并采用SABC免疫组化方法测定肝脏及末端回肠组织LFA-1的表达情况。
结果：成功建立了三组大鼠动物模型。在胆总管结扎术后第7天时,血清胆红素浓度为213.3+16.8μmol/L,第二次术后第1、3、7天时,ID组血清胆红素持续下降(ID vs SH, P<0.05),而OJ组保持高水平。ALT等酶学指标也呈相同变化。SH组肝脏病理检查显示正常肝小叶结构。胆总管结扎后7天的汇管区、小叶周边可见新生小胆管样上皮细胞,少量炎性细胞浸润；原有肝内胆管上皮细胞有少量脱落现象及少量肝细胞的坏死灶。OJ组二次开腹7天时,胆管上皮细胞增生范围增大,细胞扁平,管腔宽大,其外周基底膜及胶原纤维层增厚。ID组胆肠吻合术后7天时可见肝细胞增生,肝小叶结构逐渐恢复正常,汇管区无明显炎细胞浸润,仍可见纤维组织增生。梗阻性黄疸第7天时,大鼠血液白细胞LFA-1水平(86.97+5.52%)明显高于SH组(35.12±5.37%)(OJ vs SH, P<0.05);第二次术后第7天时,ID组白细胞LFA-1表达水平持续下降(IDvsSH, P>0.05),而OJ组保持高水平。肝脏及末端回肠组织亦有相似的结果。胆总管结扎后第7天肝脏及末端回肠免疫组化LFA-1的表达强度增加,ID组胆肠吻合术后逐渐下降,于术后第7天降至正常,与SH组比较无明显差异(IDvsSH,P>0.05)。
结论：大鼠肝脏阻塞早期即发生明显的损害,机体可产生一定的代偿以改善肝功能,但持续存在的胆管阻塞最终导致肝纤维化。大鼠阻塞性黄疸期内病理形态学的改变显示其肝功能测定值并不能反映其肝脏组织的实际损害程度。LFA-1的表达水平和梗阻性黄疸的发生、发展有显著相关性。胆道梗阻后LFA-1高水平表达,与肝功能及肝脏细胞结构损伤呈一致性,我们认为LFA-1可能在梗阻性黄疸病理生理中起到了重要作用。内引流解除术后可使肝脏及回肠病理形态基本恢复,LFA-1的表达下调。
Objective:To investigate the changes of the expression of Lymphocyte functional antigen-1 (LFA-1) in WBC, liver, distal ileum of obstructive jaundice post-released in SD rats. And to assess relationship between the increased LFA-1 expression and obstructive jaundice.
Methods:One hundred and twenty adult Sprague-Dawley rats were randomly assigned to three groups:sham operation(SH, n=40),obstructive jaundice(OJ, n=40), internal biliary drainage (ID, n=40). OJ was stablished by first operation; After seven days, ID was built by second operation. On the 7th after the first operation and 1st,3 th,7th days after the second operation, the three groups were succumbed and the specimens of blood and liver, distal ileum were collected. The level of total bilirubin(TB), albumin (ALB), alanine transminase (ALT), aspartate aminotransferase (AST) in serum and liver, distal ileum tissue to value the result of the operation.The expression of LAF-1 on WBC, liver, distal ileum tissue at different time points was detected by flow cytometry(FCM). And the LFA-1 expression of liver, distal ileum tissue was determined by SABC(Streptavidin Biotin Peroxidase complex technique) immunohistochemistry method.
Results:Rat models were successfully established. The level of total bilirubin on the 7th day after the ligation was 213.3±16.8μmol/L. On 1st,3th,7th days after the second operation, the level of total bilirubin descended(ID vs SH, P<0.05) in ID rats, but kept higher level in OJ rats. There was a similar change in the biochemical indices such as ALT. The structure of Hepatic Lobules of the SH group was normal. On 7th day after bile duct ligation, new small biliary epithelia cells appeared in the portal areas and around the liver lobulars with some inflammatory cells infiltrated; As epithelial cells of intra-hepatic bile duct exfoliated, some necrosis focuses of hepatic cells were being seen. On 7th day after the second operation, in OJ group, the hyper-plastic areas of intra-hepatic bile duct epithelial cells enlarged, the cells were flat and the lumens of the bile ducts were wide, the basal membrane and collagen fibers layers thickened. On 7th day after the second operation, in ID group, showed hyperplasia in hepatocyte, hepatic lobules gradually returned to normal, and portal area without significant inflammatory cell infiltration. But proliferation of fibrous tissue was still visible.On 7th day after bile duct ligation, the lever of LFA-1 in WBC was significantly elevated(86.97±5.52%)compared with that in SH rats (35.12±5.37%) (OJ vs SH, P<0.05).On 7th day after the second operation, the level of LFA-1 expression descended (ID vs SH, P>0.05) in ID rats, but it kept higher level in OJ rats. There was a similar change in liver and distal ileum. On 7th day after bile duct ligation, the liver and distal ileum showed the increased LFA-1 expression in OJ (OJ vs SH, P<0.05); After the second operation, the level of LFA-1 expression declined gradually, on 7th day, there were no difference between ID and SH(P>0.05).
Conclusion:There is obvious impairment in the early phase of obstructive jaundice; the liver function may be improved to a certain degree by a compensation mechanism; however, the persistence of obstructive jaundice finally leads to hepatic fibrosis. The liver function indicated by the pathomorphology changes can not reflect the actual impairment of liver tissue in obstructive jaundice rats. Increased LFA-1 expression might be related to occurrence and development of rejection. The liver dysfunction and destruction may be mediated by the consequences of LFA-1 binding. Internal drainage could relieve the expression of LFA-1.
引文
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1.黄志强,黄晓强,宋青.黄志强胆道外科手术学[M].第二版.北京.人民军医出版社.2010：64.
2. A GIACOMETTI,O CIRIONI,R GHISELLI,et al.Administration of protegrin peptide IB-367 to prevent endotoxin induced mortality in bile duct ligated rats. Gut 2003;52 (6):874-878
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4.张守华,廖彩仙,张春兴,等.小鼠梗阻性黄疸模型的建立及动态观察[J].南方医科大学学报.2008,28(9)：1579-1581.
5.孙杨忠,耿小平.阻塞性黄疸大鼠胆总管直径、压力及血清胆红素代谢变化的观察[J].肝胆外科杂志.2003,11(2)：141-142.
6.王世杰,黄强,刘臣海,等.阻塞性黄疸犬胆总管直径和压力及肝功能变化[J].中国现代普通外科进展.2009,12(12)：1020-1022.
7.STELIOS F ASSIMAKOPOULOS,CONSTANTINE E VAGIANOS.Bile duct ligation in rats: A reliable model of hepatorenal syndrome? World J Gastroenterol 2009 January 7; 15(1): 121-123.
8.刘永康,禹建峰,李智华,等.犬可复性胆总管不全梗阻对Oddi括约肌功能的影响[J].第三军医大学学报.2006,28(9)：952-954.
9.付山峰,陈文生,金博,等.兔胆总管部分结扎肝硬化模型的建立[J].天津医药.2009,37(10)：878-880.
10.张强,吴硕东,王伟.胆系不完全结扎术对家兔Oddi括约肌内NOS和VIP的影响[J].解剖科学进展.2009,15(1)：53-55.
11.夏荣龙,刘青光,姚英民,等.慢性渐进性梗阻性黄疸模型建立及评价[J].西安医科大学学报.2001,22(4)：349-350,366.
12.陈文斌,黄志强,陈永亮,等.小型猪渐进性梗阻性黄疽模型的建立[J].中华实验外科杂志.2007,24(7)：879-880.
13.王勇,陈卫民,高林林,等.多巴胺调控实验性梗阻性黄疸围手术期肾髓质水通道蛋白2表达.世界华人消化杂志.2007,15(25)：2714-2717.
14.M.T.ORUC M.M. OZMEN U.HAN. A New Technique for Inducing and Releasing Obstructive Jaundice in Rats. Eur Surg Res 2009;43:354-359
15.王彤,寇治民,王琛,等.梗阻性黄疸可重复性体内外引流模型的建立[J].医学研究生学报.2002,15(1)：62-64.
16.崔乃强,张西波,李东华,等.可控性胆道内/外引流及胆道梗阻动物模型的建立[J].中国中西医结合外科杂志.2007,13(2)：115-119.
17.王天然,周纬,黄海,等.可逆型梗阻性黄疸动物模型探讨[J].世界华人消化杂志.2005,13(126)：1454-1456.
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55.姚晋林,闫军,王世民,等.梗阻性黄疽与肠粘膜屏障功能的实验研究[J].山西医科大学学报2001,31(3)：248-250.
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1.黄志强,黄晓强,宋青.黄志强胆道外科手术学[M].第二版.北京.人民军医出版社.2010：64.
2. A GIACOMETTI,O CIRIONI,R GHISELLI,et al.Administration of protegrin peptide IB-367 to prevent endotoxin induced mortality in bile duct ligated rats. Gut 2003;52 (6):874-878
3.KOUNTOUAS J,SCHEUER PJ,BILLING BH. Effect of prolonged bile duct obstruction in the rat on hepatic transport of bilirubin [J]. Clin Sci,1985,68 (3):341-347.
4.张守华,廖彩仙,张春兴,等.小鼠梗阻性黄疸模型的建立及动态观察[J].南方医科大学学报.2008,28(9)：1579-1581.
5.孙杨忠,耿小平.阻塞性黄疸大鼠胆总管直径、压力及血清胆红素代谢变化的观察[J].肝胆外科杂志.2003,11(2)：141-142.
6.王世杰,黄强,刘臣海,等.阻塞性黄疸犬胆总管直径和压力及肝功能变化[J].中国现代普通外科进展.2009,12(12)：1020-1022.
7.STELIOS F ASSIMAKOPOULOS,CONSTANTINE E VAGIANOS.Bile duct ligation in rats: A reliable model of hepatorenal syndrome? World J Gastroenterol 2009 January 7; 15(1): 121-123.
8.刘永康,禹建峰,李智华,等.犬可复性胆总管不全梗阻对Oddi括约肌功能的影响[J].第三军医大学学报.2006,28(9)：952-954.
9.付山峰,陈文生,金博,等.兔胆总管部分结扎肝硬化模型的建立[J].天津医药.2009,37(10)：878-880.
10.张强,吴硕东,王伟.胆系不完全结扎术对家兔Oddi括约肌内NOS和VIP的影响[J].解剖科学进展.2009,15(1)：53-55.
11.夏荣龙,刘青光,姚英民,等.慢性渐进性梗阻性黄疸模型建立及评价[J].西安医科大学学报.2001,22(4)：349-350,366.
12.陈文斌,黄志强,陈永亮,等.小型猪渐进性梗阻性黄疽模型的建立[J].中华实验外科杂志.2007,24(7)：879-880.
13.王勇,陈卫民,高林林,等.多巴胺调控实验性梗阻性黄疸围手术期肾髓质水通道蛋白2表达.世界华人消化杂志.2007,15(25)：2714-2717.
14.M.T.ORUC M.M. OZMEN U.HAN. A New Technique for Inducing and Releasing Obstructive Jaundice in Rats. Eur Surg Res 2009;43:354-359
15.王彤,寇治民,王琛,等.梗阻性黄疸可重复性体内外引流模型的建立[J].医学研究生学报.2002,15(1)：62-64.
16.崔乃强,张西波,李东华,等.可控性胆道内/外引流及胆道梗阻动物模型的建立[J].中国中西医结合外科杂志.2007,13(2)：115-119.
17.王天然,周纬,黄海,等.可逆型梗阻性黄疸动物模型探讨[J].世界华人消化杂志.2005,13(126)：1454-1456.
18.张晞文,李可为,王坚,等.阻塞性黄疸大鼠内引流术后血浆内皮素和肾血流量的关系[J].肝胆胰外科杂志.2002,14(2)：104-106.
19.孙杨忠.阻塞性黄疸大鼠肝叶切除+胆肠内引流模型的制作特点[J].临床和实验医学杂志.2007,6(5)：11-12.
20.吕维富,胡曙东,王伟昱,等.经皮肝穿刺胆管-胃引流治疗梗阻性黄疸动物实验[J].实验研究.2007,16(4)：269-272.
21.肖敏,令狐恩强,李雪,等.微创可复梗阻性黄疸模型的建立[J].解放军医学杂志.2008,33(1)：77-79.
22.夏荣龙,刘青光,倪卫东,等.恶性梗阻性黄疸实验模型建立及评价[J].西安医科大学学报.2001,22(5)：480-481；491.
23.林薇,许建衡,刘婉秀,等.难治性黄疽动物模型研究[J].世界华人消化杂志.2001,9(3)；335.