NF-κB及其下游抗凋亡因子在胆道损伤愈合过程中的表达的基础研究
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摘要
目的：组织损伤愈合是一个由众多细胞、细胞因子、信号蛋白以及相关基因所参与的庞大反应体系,不同组织因内环境的差异会出现不同的愈合结局,而胆道独特的生理解剖学特点造成其瘢痕形式的愈合转归,瘢痕的挛缩将导致胆道良性狭窄的发生,继而胆汁排泄甚至分泌受阻,发生梗阻,从而引起临床上一系列的症状,最终造成胆道感染,胆汁性肝硬化,肝衰竭等结局。本课题拟建立犬胆道损伤愈合模型,通过动态观察胆管损伤修复瘢痕形成过程中核转录因子κB (Nuclear Factor Kappa B,NF-κB)激活情况及其下游凋亡调控蛋白：凋亡抑制蛋白1(cellular inhibitor of apoptosis protein-1,cIAP-1),FLICE样抑制蛋白(FLICE-like inhibitory protein,c-FLIP)及其下游凋亡因子caspase3、8的表达及定位情况,从凋亡增殖平衡角度阐述胆道损伤愈合瘢痕形成机制,为临床找到治疗胆道良性狭窄的新方法提供思路。
方法：选取本地健康杂交犬30只,随机(数字表法)分为实验组(n=15),对照组(n=15),每组再分为2月,3月,4月,5月,6月组。建立犬胆管损伤模型,采用电刀全层切开胆总管前、侧壁,保留后壁,然后均行粘膜对粘膜全层缝合,对照组游离胆总管后关腹。分别于术后各小组相应时间点取胆管吻合口组织,以免疫组织化学SP法检测NF-κB激活情况,c-FLIP蛋白及caspase3、8的表达及定位情况,用原位杂交法检测cIAP-1及c-FLIP mRNA表达情况。利用图像分析系统定量分析两组的阳性细胞数及定位,并进行统计学分析,比较。
结果：1.NF-κB于实验组内各时间点均有明显激活(37.52±4.33～50.41±4.17),较对照组(8.68±0.78～10.17±1.27)有显著性差异(P<0.05),主要定位于间质细胞,以成纤维细胞为甚；各时相间总体有显著性差异(P<0.05),其中以3月组最为强烈(50.41±4.17%)；5月组与2,3月,6月组与2,3,4月组均有差异(P<0.05)。2.实验组各时相的间质组织中cFLIPmRNA均呈强阳性表达,以纤维细胞胞浆表达为主,而腺体组织很少表达或几乎无表达；在相应时相的间质组织中(24.76±4.52～30.57±6.17)的表达明显强于在腺体组织中(3.27±1.17～3.83±1.04)的表达(P<0.05)；在间质组织或腺体组织中cFLIPmRNA表达在不同时相之间差异均无统计学意义(P>0.05)。假手术组各时相的间质组织和腺体组织中均呈弱表达；在相应时相的间质组织(3.19±0.70～3.95±1.10)和腺体组织中(3.44±0.59～3.78±0.71)cFLIPmRNA表达差异无统计学意义(P>0.05)；间质组织或腺体组织中cFLIPmRNA表达在不同时相之间差异均无统计学意义(P>0.05)。cFLIPmRNA在实验组的间质组织中的表达明显高于相应时相的假手术组(P<0.05)；而cFLIPmRNA在腺体组织中的表达两组间差异无统计学意义(P>0.05)。3.c-FLIP蛋白于实验组内各时间点均呈阳性表达,定位于间质细胞,以成纤维细胞为主,各时间点内实验组(17.23±3.53～22.33±3.40)与对照组(3.11±1.01～3.41±0.69)比较有显著性差异(P<0.05)；而各时间点之间无显著性差异(P>0.05)。caspase8于实验组(3.20±0.86～4.01±0.88)各时相均呈现弱表达,定位以腺上皮居多,间质组织表达相对较弱,与配对之对照组(10.03±1.93～11.66±2.80)比较差异显著(P<0.05)；而各时间点之间亦无显著性差异(P>0.05)。相关性分析结果：发现c-FLIP与caspase8蛋白表达成负相关(P<0.01,r=-0.94)。4.实验组cIAP1mRNA于各时间点均强阳性表达(25.85±6.61～36.85±4.21),与对照组(2.68±1.05～3.10±1.00)差异明显(P<0.05),定位于间质细胞,以成纤维细胞最为明显；各时间点间无显著性差异(P>0.05)。实验组Caspase3表达(2.65±0.60～4.37±0.62)明显弱于对照组(10.15±2.06～11.96±3.69)(P<0.05),腺上皮表达相对较强,各期之间无明显差异(P>0.05)。且cIAP-1mRNA与caspase3蛋白表达呈负相关(P<0.01,r=-0.95)。
结论：胆道(肌)成纤维细胞NF-κB的激活及其下游凋亡调控蛋白cIAP-1,c-FLIP的表达可能分别通过抑制终端凋亡执行蛋白caspase3、8激活,在胆道损伤后的瘢痕愈合转归中发挥重要作用。
Objective:Wound healing is a huge reaction system involved in a large number of cells, cytokines, signaling proteins and related genes,and the differences within the different organizations environmental may cause different healing outcomes, and the unique physiological and anatomical features of bile duct caused a form of the healing outcome of scar, scar contracture will lead to the occurrence of bile duct stenosis, and then bile excretion or secretion occurs obstruction, which led to a series of clinical symptoms, eventually leading to biliary infection, biliary cirrhosis, liver failure and other outcomes.The aim of this issue is by establishing the healing model after bile duct injury in dogs, through the dynamic observation to during the scar formation after bile duct injury, the expression and location of Nuclear Factor Kappa B activation and its downstream apoptosis regulatory protein:cellular inhibitor of apoptosis protein-1,FLICE-like inhibitory protein and their downstream apoptotic factor caspase3,8 and the mechanism of bile duct wound healing and scar formation was expounded from the point of view of the the balance of proliferation and apoptosis, in order to provide ideas to find new ways for the clinical treatment of biliary stenosis.
Methods:30 local health hybrid dogs, were randomly (number table) divided into experimental group (n=15) and control group (n=15), each further divided into 2months,3months,4months,5months,6months group.The models of wound healing after bile duct injury in dogs bying transverse to cut the whole floor of anterior wall and sides of common bile ducts using the electric knife, retaining hind wall.and then all underwent full thickness suture from mucosal to mucosa; the common bile ducts of the control group were only dissociated before that the abdomens were closed. After anastomotic bile duct tissue were drawn at the corresponding time points of each group after operations, immunohistochemistry SP method was using to detect and analysis the expression and localization of activated NF-κB,c-FLIP protein and caspase3,8,and in situ hybridization method was using to detect and analysis the expression and localization of cIAP-1 and c-FLIP mRNA expression. By image analysis system,the number of positive cells were quantitatively analysised both the groups.finally, statistically analysis and comparation were made.
Results:1.The activation of NF-KB were significant at all the time points in the experimental group, Locating in the stromal cells, especially in fibroblasts.There were more significant difference between the experimental group(37.52±4.33～50.41±4.17)and control group(8.68±0.78～10.17±1.27)at the same phase (P<0.05),and the former was significantly stronger than the latter; There were significant differences within each time point of the experimental group in totality (P<0.05).Among them, the strongest group was 3months group(50.41±4.17%);there were no differences within 2 (P>0.05)、3(P>0.05)、4(P>0.05)months groupand were differences between 5 months and 2(P<0.05)、3(P<0.05)months group;so is also between 6 months and 2(P<0.05)、3(P<0.05)、4(P<0.05)months group.2.There were all strong positive expression of cFLIPmRNA in the interstitial tissue of experimental group in all time points, mainly expressed in the cytoplasm of fibroblast and very little or almost no expression in the glandular tissue. Positive expression of cFLIPmRNA in the interstitial tissue(24.76±4.52～30.57±6.17)was significantly stronger than that of glands tissue(3.27±1.17～3.83±1.04) (P<0.05).There were no significant differences among each time point in either the interstitial tissue or glandular tissue (P>0.05).There were all weak expressions in the interstitial tissue(3.19±0.70～3.95±1.10)and glandular tissue(3.44±0.59～3.78±0.71)of the sham operation group at all time points and was no significant difference (P>0.05),no difference between each phase (P>0.05);The expression of the experimental group was significant (P<0.05) compared with sham operation group in the interstitial tissue at all time, while no that in the glandular tissue (P>0.05)3.There were all strong positive expression of c-FLIP protein in the anastomotic tissue of the experimental group at all time points(17.23±3.53～22.33±3.40),mainly expressed in the cytoplasm of fibroblastand very little or almost no expression in the glandular tissue. There were more significant difference between the experimental group and control group(3.11±1.01～3.41±0.69) at the same phase (P<0.05),and the former was significantly stronger than the latter; There were all weak expression of caspase8 in the anastomotic tissue(3.20±0.86～4.01±0.88)of the experimental group at all time points,significantly different compared with the control group(10.03±1.93～11.66±2.80)at the same phase(P<0.05;and there were no significant differences among all the time points(P>0.05).The expression of caspase8 in the experimental group showed poor. Most targeted to epithelial and stromal tissue is relatively less.The results of the correlation analysis:There was negative correlation in the expression between c-FLIP and caspase8 (P<0.01, r=-0.94).4.The expression of cIAP1mRNA in the anastomotic tissue of experimental group(25.85±6.61～36.85±4.21)were more significant compared with the control group(2.68±1.05～3.10±1.00)at all the time points (P<0.05),located in the interstitial cells, especially in fibroblasts; there was no significant difference among all the stages (P>0.05).The expression of Caspase3 in the anastomotic tissue of experimental group (2.65±0.60～4.37±0.62)were significantly less than the control group (10.15±2.06～11.96±3.69)(P<0.05),the expression located in epithelial was relatively stronger and there was no significant difference among all the phases (P>0.05).There was negative correlation between cIAP-1 mRNA and caspase3 protein in expression (P<0.01, r=-0.95).
Conclusion:The activation of NF-κB and the expression of its downstream apoptosis protein cIAP-1,c-FLIP of bile duct (muscle) fibroblasts may play an important role in bile duct scar healing after injury by respectively inhibiting the activation of terminal proteins of executive apoptosis caspase3,8.
方法：选取本地健康杂交犬30只,随机(数字表法)分为实验组(n=15),对照组(n=15),每组再分为2月,3月,4月,5月,6月组。建立犬胆管损伤模型,采用电刀全层切开胆总管前、侧壁,保留后壁,然后均行粘膜对粘膜全层缝合,对照组游离胆总管后关腹。分别于术后各小组相应时间点取胆管吻合口组织,以免疫组织化学SP法检测NF-κB激活情况,c-FLIP蛋白及caspase3、8的表达及定位情况,用原位杂交法检测cIAP-1及c-FLIP mRNA表达情况。利用图像分析系统定量分析两组的阳性细胞数及定位,并进行统计学分析,比较。
结果：1.NF-κB于实验组内各时间点均有明显激活(37.52±4.33～50.41±4.17),较对照组(8.68±0.78～10.17±1.27)有显著性差异(P<0.05),主要定位于间质细胞,以成纤维细胞为甚；各时相间总体有显著性差异(P<0.05),其中以3月组最为强烈(50.41±4.17%)；5月组与2,3月,6月组与2,3,4月组均有差异(P<0.05)。2.实验组各时相的间质组织中cFLIPmRNA均呈强阳性表达,以纤维细胞胞浆表达为主,而腺体组织很少表达或几乎无表达；在相应时相的间质组织中(24.76±4.52～30.57±6.17)的表达明显强于在腺体组织中(3.27±1.17～3.83±1.04)的表达(P<0.05)；在间质组织或腺体组织中cFLIPmRNA表达在不同时相之间差异均无统计学意义(P>0.05)。假手术组各时相的间质组织和腺体组织中均呈弱表达；在相应时相的间质组织(3.19±0.70～3.95±1.10)和腺体组织中(3.44±0.59～3.78±0.71)cFLIPmRNA表达差异无统计学意义(P>0.05)；间质组织或腺体组织中cFLIPmRNA表达在不同时相之间差异均无统计学意义(P>0.05)。cFLIPmRNA在实验组的间质组织中的表达明显高于相应时相的假手术组(P<0.05)；而cFLIPmRNA在腺体组织中的表达两组间差异无统计学意义(P>0.05)。3.c-FLIP蛋白于实验组内各时间点均呈阳性表达,定位于间质细胞,以成纤维细胞为主,各时间点内实验组(17.23±3.53～22.33±3.40)与对照组(3.11±1.01～3.41±0.69)比较有显著性差异(P<0.05)；而各时间点之间无显著性差异(P>0.05)。caspase8于实验组(3.20±0.86～4.01±0.88)各时相均呈现弱表达,定位以腺上皮居多,间质组织表达相对较弱,与配对之对照组(10.03±1.93～11.66±2.80)比较差异显著(P<0.05)；而各时间点之间亦无显著性差异(P>0.05)。相关性分析结果：发现c-FLIP与caspase8蛋白表达成负相关(P<0.01,r=-0.94)。4.实验组cIAP1mRNA于各时间点均强阳性表达(25.85±6.61～36.85±4.21),与对照组(2.68±1.05～3.10±1.00)差异明显(P<0.05),定位于间质细胞,以成纤维细胞最为明显；各时间点间无显著性差异(P>0.05)。实验组Caspase3表达(2.65±0.60～4.37±0.62)明显弱于对照组(10.15±2.06～11.96±3.69)(P<0.05),腺上皮表达相对较强,各期之间无明显差异(P>0.05)。且cIAP-1mRNA与caspase3蛋白表达呈负相关(P<0.01,r=-0.95)。
结论：胆道(肌)成纤维细胞NF-κB的激活及其下游凋亡调控蛋白cIAP-1,c-FLIP的表达可能分别通过抑制终端凋亡执行蛋白caspase3、8激活,在胆道损伤后的瘢痕愈合转归中发挥重要作用。
Objective:Wound healing is a huge reaction system involved in a large number of cells, cytokines, signaling proteins and related genes,and the differences within the different organizations environmental may cause different healing outcomes, and the unique physiological and anatomical features of bile duct caused a form of the healing outcome of scar, scar contracture will lead to the occurrence of bile duct stenosis, and then bile excretion or secretion occurs obstruction, which led to a series of clinical symptoms, eventually leading to biliary infection, biliary cirrhosis, liver failure and other outcomes.The aim of this issue is by establishing the healing model after bile duct injury in dogs, through the dynamic observation to during the scar formation after bile duct injury, the expression and location of Nuclear Factor Kappa B activation and its downstream apoptosis regulatory protein:cellular inhibitor of apoptosis protein-1,FLICE-like inhibitory protein and their downstream apoptotic factor caspase3,8 and the mechanism of bile duct wound healing and scar formation was expounded from the point of view of the the balance of proliferation and apoptosis, in order to provide ideas to find new ways for the clinical treatment of biliary stenosis.
Methods:30 local health hybrid dogs, were randomly (number table) divided into experimental group (n=15) and control group (n=15), each further divided into 2months,3months,4months,5months,6months group.The models of wound healing after bile duct injury in dogs bying transverse to cut the whole floor of anterior wall and sides of common bile ducts using the electric knife, retaining hind wall.and then all underwent full thickness suture from mucosal to mucosa; the common bile ducts of the control group were only dissociated before that the abdomens were closed. After anastomotic bile duct tissue were drawn at the corresponding time points of each group after operations, immunohistochemistry SP method was using to detect and analysis the expression and localization of activated NF-κB,c-FLIP protein and caspase3,8,and in situ hybridization method was using to detect and analysis the expression and localization of cIAP-1 and c-FLIP mRNA expression. By image analysis system,the number of positive cells were quantitatively analysised both the groups.finally, statistically analysis and comparation were made.
Results:1.The activation of NF-KB were significant at all the time points in the experimental group, Locating in the stromal cells, especially in fibroblasts.There were more significant difference between the experimental group(37.52±4.33～50.41±4.17)and control group(8.68±0.78～10.17±1.27)at the same phase (P<0.05),and the former was significantly stronger than the latter; There were significant differences within each time point of the experimental group in totality (P<0.05).Among them, the strongest group was 3months group(50.41±4.17%);there were no differences within 2 (P>0.05)、3(P>0.05)、4(P>0.05)months groupand were differences between 5 months and 2(P<0.05)、3(P<0.05)months group;so is also between 6 months and 2(P<0.05)、3(P<0.05)、4(P<0.05)months group.2.There were all strong positive expression of cFLIPmRNA in the interstitial tissue of experimental group in all time points, mainly expressed in the cytoplasm of fibroblast and very little or almost no expression in the glandular tissue. Positive expression of cFLIPmRNA in the interstitial tissue(24.76±4.52～30.57±6.17)was significantly stronger than that of glands tissue(3.27±1.17～3.83±1.04) (P<0.05).There were no significant differences among each time point in either the interstitial tissue or glandular tissue (P>0.05).There were all weak expressions in the interstitial tissue(3.19±0.70～3.95±1.10)and glandular tissue(3.44±0.59～3.78±0.71)of the sham operation group at all time points and was no significant difference (P>0.05),no difference between each phase (P>0.05);The expression of the experimental group was significant (P<0.05) compared with sham operation group in the interstitial tissue at all time, while no that in the glandular tissue (P>0.05)3.There were all strong positive expression of c-FLIP protein in the anastomotic tissue of the experimental group at all time points(17.23±3.53～22.33±3.40),mainly expressed in the cytoplasm of fibroblastand very little or almost no expression in the glandular tissue. There were more significant difference between the experimental group and control group(3.11±1.01～3.41±0.69) at the same phase (P<0.05),and the former was significantly stronger than the latter; There were all weak expression of caspase8 in the anastomotic tissue(3.20±0.86～4.01±0.88)of the experimental group at all time points,significantly different compared with the control group(10.03±1.93～11.66±2.80)at the same phase(P<0.05;and there were no significant differences among all the time points(P>0.05).The expression of caspase8 in the experimental group showed poor. Most targeted to epithelial and stromal tissue is relatively less.The results of the correlation analysis:There was negative correlation in the expression between c-FLIP and caspase8 (P<0.01, r=-0.94).4.The expression of cIAP1mRNA in the anastomotic tissue of experimental group(25.85±6.61～36.85±4.21)were more significant compared with the control group(2.68±1.05～3.10±1.00)at all the time points (P<0.05),located in the interstitial cells, especially in fibroblasts; there was no significant difference among all the stages (P>0.05).The expression of Caspase3 in the anastomotic tissue of experimental group (2.65±0.60～4.37±0.62)were significantly less than the control group (10.15±2.06～11.96±3.69)(P<0.05),the expression located in epithelial was relatively stronger and there was no significant difference among all the phases (P>0.05).There was negative correlation between cIAP-1 mRNA and caspase3 protein in expression (P<0.01, r=-0.95).
Conclusion:The activation of NF-κB and the expression of its downstream apoptosis protein cIAP-1,c-FLIP of bile duct (muscle) fibroblasts may play an important role in bile duct scar healing after injury by respectively inhibiting the activation of terminal proteins of executive apoptosis caspase3,8.
引文
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20.Xuefeng Xia, Heather Francis, Shannon Glaser,et al. Bile acid interactions with cholangiocytes [J].World J Gastroenterol,2006;12(22):3553-3563.
21.Alain Lilienbaum,Alain Israel. From Calcium to NF-kB Signaling Pathways in Neurons [J].Molecular and Cellular Biology,2003;23(8):2680-2698.
22.C.M.Payne,C.Weber, C.Crowley-Skillicorn,et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kB through multiple mech-anisms in HCT-116 colon epithelial cells [J]. Carcinogenesis,2007;28 (1): 215-222.
23.Hirano F, Haneda M, Makino I,et al. Chenodeoxycholic acid and taurochen-odexycholic acid induce anti-apoptotic cIAP-1 expression in human heap to-cytes[J].J Gastroenterol Hepatol,2006;21(12):1807-13.
24.Lamireau T, Zoltowska M, Levy E, et al. Effects of bile acids on biliary epithelial cells:proliferation, cytotoxicity,and cytokine secretion [J].Life Sci,2003;72(12):1401-11.
25.Turner DJ, Alaish SM, Zou T, et al. Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression [J].Ann Surg,2007;245(3): 415-25.
26.Imoto I, Yang ZQ, Pimkhaokham A, et al. Identification of cIAP1 As a Can-didate Target Gene within an Amplicon at 11q22 in Esophageal Squamous Cell Carcinomas1 [J].Cancer Res,2001;61(18):6629-34.
27.Chen W,Fu XB,Ces L,et al.Development of gene microarry in screening differently expressed genes in keloid and normal-control skin[J].Clin Med J(Edgl),2004,117(6):877-881.
28.Messadi DV,LEA Berc S.Expression of apoptosis-associated gene by human dermal sear fibroblasts [J].Wound Repair Regen,1999,7(6):511-517.
29.Banno T, Gazel A, Blumenberg M. Pathway specific profiling identifies the NF-kappa B dependent tumor necrosis factor alpha regulated genes in epidermal keratinocytes [J].J Biol Chem,2005;280(19):18973-18980.
30.刘晋西,岑瑛.细胞凋亡与病理性瘢痕的研究进展[J].西部医学,2004；16(4)：364-366.
31.Nicholson D W, Thonberry N A.Caspases:Killer proteases [J].TIBS,199 7;22(8):299-306.
32.Papa S,Zazzeroni F, Pham CG, et al. Linking JNK signaling to NF-kappaB: a key to survival [J].J Cell Sci,2004;117(Pt 22):5197-208.
33.高文超,孙延平,阮灿平等。cFLIP在大肠癌组织中的表达及意义[J]。中国普外基础与临床杂志,2009；12(3)：218-222.
34.Djerbi M, Darreh Shori T, Zhivotovsky B,et al. Characterization of the hu-man FLICE inhibitory protein locus and comparison of the antiapoptotic activity of four different flip isoforms [J].Scand J Immunol,2001;54(12): 180-189.
35.Bodmer JL, Schroter M, Burns K, et al. Inhibition of death receptor signals by cellular FLIP[J].Nature,1997;388(6638):190-195.
36.Ha JE, Choi YE, Jang J, et al. FLIP and MAPK play crucial roles in the ML-N51 mediated hyperproliferation of fibroblast like synoviocytes in the pathogenesis of rheumatoid arthritis[J].FEBS J,2008;275(14):3546-3555.
37.Jiang T, Han Z, Chen S,et al. Resistance to activation induced cell death and elevated FLIPL expression of CD4+ T cells in a polyI：C induced pri-mary biliary cirrhosis mouse model[J].Clin Exp Med,2009;9(4):269-276.
38.Lee SH, Kim HS,Kim SY, et al. Increased expression of FLIP, an Inhibitor of Fas-mediated apoptosis, in stomach cancer[J].APMIS,2003;111(2):309-14.
39.Mori T,Doi R,Kida A,et al.Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells[J].J Surg Res,2007;142(2): 281-6.
40.Pajak B,Orzechowski A. FLIP--an enemy which might lose the battle against the specifc inhibitors of translation[J].Postepy Hig Med Dosw (Online),2005;59:140-149
41.何贵金,高沁怡,许书河,等.103钯支架诱导犬胆管增殖平滑肌细胞凋亡与防治胆管狭窄关系研究[J].中国普外基础与临床杂志,2005；12(4)：340-342.
42.Yang JK. FLIP as an anti cancer therapeutic target[J].Yonsei Med J,2008; 49(1):19-27.
43.Kreuz S,Siegmund D, Scheurich P, et al. NF-kappaB inducers upregulate cFLIP, a cycloheximide sensitive inhibitor of death receptor signaling[J]. Mol Cell Biol,2001;21(12):3964-3973.
44.Pawar P, Ma L, Byon CH, et al. Molecular mechanisms of tamoxifen therapy for cholangiocarcinoma:role of calmodulin[J]. Clin Cancer Res, 2009;15(4):1288-1296.
1.Archer S B,Brown D W, Smith C D et al.Bile duct injury during laparoscopic cholecystectomy:results of a national survey[J].Ann Surg, 2001;234(4):549-559.
2.Geng Z M, Yao Y M, Liu Q G,et al. Mechanism of benign biliary stricture: a morphological and immunohistochemical study[J].World J Gastroenterol, 2005;11(2):293-5.
3.Lin Z Q, Kondo T, Ishida Y, et al.Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice[J].Journal of Leukocyte Biology,2003;73(6):713-721.
4.Graves D T, Nooh N, Gillen T, et al.IL-1 Plays a Critical Role in Oral, But Not Dermal, Wound Healing[J].The.Journal of Immunology,2001;167(9): 5316-5320.
5.Mann A, Niekisch K, Schirmacher P, et al. Granulocyte-macrophage colony-stimulating factor is essential for normal wound healing. [J].J Investig Dermatol Symp Proc,2006;11(1):87-92.
6.Kisseleva T, Brenner D A. Mechanisms of fibrogenesis[J].Exp Biol Med (Maywood),2008;233(2):109-22.
7.Geng Z M,Zheng J B, Zhang X X, et al. Role of transforming growth factor-beta signaling pathway in pathogenesis of benign biliary stricture[J]. World J Gastroenterol,2008;14(31):4949-54.
8.Schoenborn JR, Wilson CB.Regulation of interferon-gamma during innate and adaptive immune responses[J].Adv Immunol,2007;96:41-101.
9.Sobral L M,Montan P F, Martelli-Junior H, et al Opposite effects of TGF-betal and IFN-gamma on transdifferentiation of myofibroblast in human gingival cell cultures[J],J Clin Periodontol,2007;34(5):397-406.
10.Ghosh AK, Varga J. The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis.[J].J Cell Physiol,2007;213(3): 663-71.
11.王秋实,吴德全,孙凌宇.γ-干扰素对兔胆总管愈合过程中α-平滑肌动蛋白表达的影响[J].哈尔滨医科大学学报,2006；40(1)：33-35.
12.Leask A, Abraham D J. TGF-βsignaling and the fibrotic response[J].FASEB J,2004;18(7):816-27.
13.Uitto J. IL-6 signaling pathway in keloids:a target for pharmacologic intervention[J]?J Invest Dermatol,2007;127(1):6-8.
14.Nozaki I,Lunz J QSpecht S,et al. Regulation and function of trefoil factor family 3 expression in the biliary tree[J].Am J Pathol,2004;165(6):1907-1920.
15.Demetris A J, Specht S,Nozaki l,et al. Small Proline Rich Proteins (SPRR) Function as SH3 Domain Ligands, Increase Resistance to Injury and are Associated with Epithelial-Mesenchymal Transition (EMT) in chol angio-cytes[J].J Hepatol,2008;48(2):276-88.
16.张刚,谭军,李高峰。细胞因子抗瘢痕的研究进展[J]。现代生物医学进展,2008；8(6),1175-1177.
17.徐勇,耿智敏,王居.碱性成纤维细胞生长因子对胆肠吻合口愈合的影响[J].中国修复重建外科杂志,2005；19(5)：341-343.
18.Akasaka Y, Ono I, Tominaga A, et al. Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of alpha-smooth muscle actin, leading to reduction of wound contraction[J].Wound Repair Regen.2007;15(3):378-89.
19.辛宏,颜光涛,陈泮藻.生物膜信号转导与细胞凋亡[J].生物化学与生物物理进展,2001；28(1)：52-55.
20. Lu F, Gao J, Ogawa R,et al. Fas-mediated apoptotic signal transduction in keloid and hypertrophic scar[J].Plast Reconstr Surg,2007;119(6):1714-21.
21.Wesemann D R,Qin H,Kokorana N,et al.TRADD interacts with STAT1-alpha and influences interferon-gamma signaling[J].Nature Immunol,2004; 5(2):199-207.
22.Lee N K, Lee S Y. Modulation of life and death by the tumor necrosis factorreceptor-associated factors(TRAFs)[J].J Biochem Mol Biol,200 2;35(1):61-66.
23.Sharma V, Tewari R, Sk U H, et al. Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formatio n of death inducing signaling complex[J].Int J Cancer,2008;123(9):2204 -2212.
24.Messadi D V, Doung H S,Zhang Q,et al.Activation of NFkappaB signal pathways in keloid fibroblasts[J].Arch Dermatol Res,2004;296(3):125-33.
25.Shahram A,Kirit A,Yubin S,et al. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis[J].The FASEB Journal· Research Communication,2007;21:3250-3261.
26.Gottlieb T M,Leal J F,Seger R,et al. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis[J],Oncogene,2002;21 (8):1299-1303.
27.Akasaka Y, Ono I,Yamashita T,et al. Basic fibroblast growth factor promotes apoptosis and suppresses granulation tissue formation in acute incisional wounds[J].J Pathol,2004;203(2):710-20.
28.Demetris A J,Lunz J QSpecht S,et al. Biliary wound healing, ductular reactions,and IL-6/gp130 signaling in the development of liver disease[J]. World J Gastroenterol,2006;12(22):3512-3522。
29.Yoshioka K, Mori A, Taniguchi K, et al. Cell proliferation activity of proliferating bile duct after bile duct ligation in rats[J].Vet Pathol,2005;42 (3):382-5.
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38.沈锐,利天增.组织缺氧与增生性瘢痕的关系[J].国际外科学杂志,2006；33(1)：70-73.
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5.Messadi DV, Doung HS,Zhang Q,et al.Activation of NFkappaB signal path-ways in keloid fibroblasts[J].Arch Dermatol Res,2004;296(3):125-33.
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11.K. Campbell, S.Rocha, N. Perkins, et al. Active Repression of Antiapoptotic Gene Expression by RelA(p65) NF-κB [J].Molecular Cell,2004;13(6):853-865
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14.Kristiansen TZ, Bunkenborg J, Gronborg M, et al. A proteomic analysis of human bile[J].Mol Cell Proteomics,2004;3(7):715-28.
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16.耿智敏,张晓雪,王林,陶杰.良性胆管狭窄组织中CTGF表达的意义[J].第四军医大学学报,2007；28(21)：1591,2591,3591.
17.Kosters A, Karpen SJ. Bile acid transporters in health and disease [J]. Xenobiotica,2008;38(7-8):1043-71.
18.Pellicoro A, Faber KN.Review article:The function and regulation of prot-eins involved in bile salt biosynthesis and transport [J].Aliment Pharmacol Ther,2007;26 (2):149-60.
19.Alrefai WA, Gill RK. Bile acid transporters:structure, function, regulation and pathophysiological implications [J].Pharm Res.2007;24(10):1803-23.
20.Xuefeng Xia, Heather Francis, Shannon Glaser,et al. Bile acid interactions with cholangiocytes [J].World J Gastroenterol,2006;12(22):3553-3563.
21.Alain Lilienbaum,Alain Israel. From Calcium to NF-kB Signaling Pathways in Neurons [J].Molecular and Cellular Biology,2003;23(8):2680-2698.
22.C.M.Payne,C.Weber, C.Crowley-Skillicorn,et al. Deoxycholate induces mitochondrial oxidative stress and activates NF-kB through multiple mech-anisms in HCT-116 colon epithelial cells [J]. Carcinogenesis,2007;28 (1): 215-222.
23.Hirano F, Haneda M, Makino I,et al. Chenodeoxycholic acid and taurochen-odexycholic acid induce anti-apoptotic cIAP-1 expression in human heap to-cytes[J].J Gastroenterol Hepatol,2006;21(12):1807-13.
24.Lamireau T, Zoltowska M, Levy E, et al. Effects of bile acids on biliary epithelial cells:proliferation, cytotoxicity,and cytokine secretion [J].Life Sci,2003;72(12):1401-11.
25.Turner DJ, Alaish SM, Zou T, et al. Bile salts induce resistance to apoptosis through NF-kappaB-mediated XIAP expression [J].Ann Surg,2007;245(3): 415-25.
26.Imoto I, Yang ZQ, Pimkhaokham A, et al. Identification of cIAP1 As a Can-didate Target Gene within an Amplicon at 11q22 in Esophageal Squamous Cell Carcinomas1 [J].Cancer Res,2001;61(18):6629-34.
27.Chen W,Fu XB,Ces L,et al.Development of gene microarry in screening differently expressed genes in keloid and normal-control skin[J].Clin Med J(Edgl),2004,117(6):877-881.
28.Messadi DV,LEA Berc S.Expression of apoptosis-associated gene by human dermal sear fibroblasts [J].Wound Repair Regen,1999,7(6):511-517.
29.Banno T, Gazel A, Blumenberg M. Pathway specific profiling identifies the NF-kappa B dependent tumor necrosis factor alpha regulated genes in epidermal keratinocytes [J].J Biol Chem,2005;280(19):18973-18980.
30.刘晋西,岑瑛.细胞凋亡与病理性瘢痕的研究进展[J].西部医学,2004；16(4)：364-366.
31.Nicholson D W, Thonberry N A.Caspases:Killer proteases [J].TIBS,199 7;22(8):299-306.
32.Papa S,Zazzeroni F, Pham CG, et al. Linking JNK signaling to NF-kappaB: a key to survival [J].J Cell Sci,2004;117(Pt 22):5197-208.
33.高文超,孙延平,阮灿平等。cFLIP在大肠癌组织中的表达及意义[J]。中国普外基础与临床杂志,2009；12(3)：218-222.
34.Djerbi M, Darreh Shori T, Zhivotovsky B,et al. Characterization of the hu-man FLICE inhibitory protein locus and comparison of the antiapoptotic activity of four different flip isoforms [J].Scand J Immunol,2001;54(12): 180-189.
35.Bodmer JL, Schroter M, Burns K, et al. Inhibition of death receptor signals by cellular FLIP[J].Nature,1997;388(6638):190-195.
36.Ha JE, Choi YE, Jang J, et al. FLIP and MAPK play crucial roles in the ML-N51 mediated hyperproliferation of fibroblast like synoviocytes in the pathogenesis of rheumatoid arthritis[J].FEBS J,2008;275(14):3546-3555.
37.Jiang T, Han Z, Chen S,et al. Resistance to activation induced cell death and elevated FLIPL expression of CD4+ T cells in a polyI：C induced pri-mary biliary cirrhosis mouse model[J].Clin Exp Med,2009;9(4):269-276.
38.Lee SH, Kim HS,Kim SY, et al. Increased expression of FLIP, an Inhibitor of Fas-mediated apoptosis, in stomach cancer[J].APMIS,2003;111(2):309-14.
39.Mori T,Doi R,Kida A,et al.Effect of the XIAP inhibitor Embelin on TRAIL-induced apoptosis of pancreatic cancer cells[J].J Surg Res,2007;142(2): 281-6.
40.Pajak B,Orzechowski A. FLIP--an enemy which might lose the battle against the specifc inhibitors of translation[J].Postepy Hig Med Dosw (Online),2005;59:140-149
41.何贵金,高沁怡,许书河,等.103钯支架诱导犬胆管增殖平滑肌细胞凋亡与防治胆管狭窄关系研究[J].中国普外基础与临床杂志,2005；12(4)：340-342.
42.Yang JK. FLIP as an anti cancer therapeutic target[J].Yonsei Med J,2008; 49(1):19-27.
43.Kreuz S,Siegmund D, Scheurich P, et al. NF-kappaB inducers upregulate cFLIP, a cycloheximide sensitive inhibitor of death receptor signaling[J]. Mol Cell Biol,2001;21(12):3964-3973.
44.Pawar P, Ma L, Byon CH, et al. Molecular mechanisms of tamoxifen therapy for cholangiocarcinoma:role of calmodulin[J]. Clin Cancer Res, 2009;15(4):1288-1296.
1.Archer S B,Brown D W, Smith C D et al.Bile duct injury during laparoscopic cholecystectomy:results of a national survey[J].Ann Surg, 2001;234(4):549-559.
2.Geng Z M, Yao Y M, Liu Q G,et al. Mechanism of benign biliary stricture: a morphological and immunohistochemical study[J].World J Gastroenterol, 2005;11(2):293-5.
3.Lin Z Q, Kondo T, Ishida Y, et al.Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice[J].Journal of Leukocyte Biology,2003;73(6):713-721.
4.Graves D T, Nooh N, Gillen T, et al.IL-1 Plays a Critical Role in Oral, But Not Dermal, Wound Healing[J].The.Journal of Immunology,2001;167(9): 5316-5320.
5.Mann A, Niekisch K, Schirmacher P, et al. Granulocyte-macrophage colony-stimulating factor is essential for normal wound healing. [J].J Investig Dermatol Symp Proc,2006;11(1):87-92.
6.Kisseleva T, Brenner D A. Mechanisms of fibrogenesis[J].Exp Biol Med (Maywood),2008;233(2):109-22.
7.Geng Z M,Zheng J B, Zhang X X, et al. Role of transforming growth factor-beta signaling pathway in pathogenesis of benign biliary stricture[J]. World J Gastroenterol,2008;14(31):4949-54.
8.Schoenborn JR, Wilson CB.Regulation of interferon-gamma during innate and adaptive immune responses[J].Adv Immunol,2007;96:41-101.
9.Sobral L M,Montan P F, Martelli-Junior H, et al Opposite effects of TGF-betal and IFN-gamma on transdifferentiation of myofibroblast in human gingival cell cultures[J],J Clin Periodontol,2007;34(5):397-406.
10.Ghosh AK, Varga J. The transcriptional coactivator and acetyltransferase p300 in fibroblast biology and fibrosis.[J].J Cell Physiol,2007;213(3): 663-71.
11.王秋实,吴德全,孙凌宇.γ-干扰素对兔胆总管愈合过程中α-平滑肌动蛋白表达的影响[J].哈尔滨医科大学学报,2006；40(1)：33-35.
12.Leask A, Abraham D J. TGF-βsignaling and the fibrotic response[J].FASEB J,2004;18(7):816-27.
13.Uitto J. IL-6 signaling pathway in keloids:a target for pharmacologic intervention[J]?J Invest Dermatol,2007;127(1):6-8.
14.Nozaki I,Lunz J QSpecht S,et al. Regulation and function of trefoil factor family 3 expression in the biliary tree[J].Am J Pathol,2004;165(6):1907-1920.
15.Demetris A J, Specht S,Nozaki l,et al. Small Proline Rich Proteins (SPRR) Function as SH3 Domain Ligands, Increase Resistance to Injury and are Associated with Epithelial-Mesenchymal Transition (EMT) in chol angio-cytes[J].J Hepatol,2008;48(2):276-88.
16.张刚,谭军,李高峰。细胞因子抗瘢痕的研究进展[J]。现代生物医学进展,2008；8(6),1175-1177.
17.徐勇,耿智敏,王居.碱性成纤维细胞生长因子对胆肠吻合口愈合的影响[J].中国修复重建外科杂志,2005；19(5)：341-343.
18.Akasaka Y, Ono I, Tominaga A, et al. Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of alpha-smooth muscle actin, leading to reduction of wound contraction[J].Wound Repair Regen.2007;15(3):378-89.
19.辛宏,颜光涛,陈泮藻.生物膜信号转导与细胞凋亡[J].生物化学与生物物理进展,2001；28(1)：52-55.
20. Lu F, Gao J, Ogawa R,et al. Fas-mediated apoptotic signal transduction in keloid and hypertrophic scar[J].Plast Reconstr Surg,2007;119(6):1714-21.
21.Wesemann D R,Qin H,Kokorana N,et al.TRADD interacts with STAT1-alpha and influences interferon-gamma signaling[J].Nature Immunol,2004; 5(2):199-207.
22.Lee N K, Lee S Y. Modulation of life and death by the tumor necrosis factorreceptor-associated factors(TRAFs)[J].J Biochem Mol Biol,200 2;35(1):61-66.
23.Sharma V, Tewari R, Sk U H, et al. Ebselen sensitizes glioblastoma cells to Tumor Necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formatio n of death inducing signaling complex[J].Int J Cancer,2008;123(9):2204 -2212.
24.Messadi D V, Doung H S,Zhang Q,et al.Activation of NFkappaB signal pathways in keloid fibroblasts[J].Arch Dermatol Res,2004;296(3):125-33.
25.Shahram A,Kirit A,Yubin S,et al. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis[J].The FASEB Journal· Research Communication,2007;21:3250-3261.
26.Gottlieb T M,Leal J F,Seger R,et al. Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis[J],Oncogene,2002;21 (8):1299-1303.
27.Akasaka Y, Ono I,Yamashita T,et al. Basic fibroblast growth factor promotes apoptosis and suppresses granulation tissue formation in acute incisional wounds[J].J Pathol,2004;203(2):710-20.
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