缺血型胆道损伤对大鼠肝移植胆道超微结构及微循环的影响及生长激素的保护作用
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摘要
缺血型胆道损伤的防护对于改善移植肝胆道血供,提高肝移植后的成功率具有重要意义。缺血型胆道损伤是一个由多因素参与的复杂的病理过程,移植肝胆道的血供主要来自肝动脉,最终肝动脉的狭窄或闭塞发挥着重要作用。重组人生长激素对组织缺血性损伤具有保护作用,有增加机体蛋白合成能力、改善机体免疫功能、降低应激反应,及刺激胰岛素样生长因子Ⅰ生成增加等诸多功能。本课题利用简便实用的大鼠自体原位肝移植模型,并造成缺血型胆道损伤,应用重组人生长激素进行术后干预,术后观察肝内胆道超微结构及微循环的变化和胆管上皮细胞凋亡、增生及相关调控因子的表达情况,研究探讨重组人生长激素对肝移植缺血型胆道损伤的防护作用及相关机制,为生长激素应用于肝移植后的胆道保护提供理论研究和实验基础。国内国外,此方面的工作尚无文献报道及有关记载。
第一部分缺血型胆道损伤对肝移植胆道超微结构的影响及生长激素的保护作用
目的：应用重组人生长激素,对大鼠自体原位肝移植术后缺血型胆道损伤进行术后干预,观察胆道超微结构改变,探讨生长激素对肝移植缺血型胆道损伤的保护作用与机制。
材料与方法：
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速获取左肝外叶胆道组织,部分置于10%多聚甲醛溶液以备光镜检查,部分置于2.5%戊二醛固定液中以备透射电镜分析。
3.检测指标
(1)胆道组织病理检测取上述10%多聚甲醛所固定组织,稍加修整,制成组织蜡块、切片,常规HE染色。高倍镜视野下,观察胆管上皮水肿、炎细胞浸润、上皮坏死脱落等情况。
(2)胆道透射电镜观察及图像分析取上述2.5%戊二醛所固定组织,制成电镜标本,电镜观察各组胆管上皮微观结构改变,并用图像分析系统对其损伤程度进行定量分析。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果
1.胆管组织学变化HE染色显示,CON组以胆管上皮水肿、炎细胞浸润等可逆性损伤为主；ITBL组以上皮大部分坏死脱落等不可逆损伤为主；而rhGH组,胆道上皮坏死脱落明显减少,以胆管上皮水肿、炎细胞浸润为主。
2.透射电镜观察术后1周CON组可见胆管的粘膜皱褶饱满,起伏自然,无上皮层破损,胆管上皮细胞呈圆形或椭圆形,形态规则,大小均一,排列整齐,表面微绒毛较丰富；ITBL组可见胆管上皮细胞呈蜂窝状坏死,基层胶原纤维裸露,残余上皮细胞欠规则,间距较大,表面微绒毛稀疏；rhGH组可见细胞数量增多,形态基本正常,细胞间距基本正常,表面微绒毛丰富但形态欠均匀。
3.胆管上皮透射电镜图像分析ITBL组的胆管上皮细胞面积密度、数密度和微绒毛面积密度等平面计量学参数均显著小于CON组和rhGH组(P<0.05)；rhGH组的胆管上皮细胞平面计量学参数较ITBL组有明显改善(P<0.05),但仍较CON组低(P<0.05)。
第二部分缺血型胆道损伤对肝移植胆道微循环的影响及生长激素的保护作用
目的：应用重组人生长激素,对大鼠自体原位肝移植术后缺血型胆道损伤进行术后干预,观察肝内胆道微循环变化,探讨生长激素对肝移植缺血型胆道损伤的保护作用与机制。
材料与方法：
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速获取左肝外叶胆道组织,置于10%多聚甲醛溶液以备石蜡切片。
3.检测指标
(1)病理学检查：石蜡标本2.5μm切片,常规HE染色。观察汇管区炎症细胞浸润及胆管结构破坏程度。
(2)石蜡标本2.5μm连续切片,用兔抗CD34多克隆抗体标记血管。计数汇管区胆管数、血管数、伴有血管的胆管数、不伴有血管的胆管数及孤立的血管数。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果1.胆管病理形态观察ITBL组胆管上皮细胞排列明显缺失,管壁无增厚,汇管区也无明显炎症细胞浸润。CON组、rhGH组胆管上皮细胞呈慢性增生性炎症改变,管壁明显增厚,汇管区炎性细胞增多,胆管上皮细胞增生2.汇管区胆管及血管的变化胆道缺血性损伤后,汇管区胆管受损,ITBL组较CON组汇管区胆管数明显减少(P<0.05); rhGH处理后,汇管区胆管增生,rhGH组较ITBL组汇管区胆管数明显增加(P<0.05)。缺血型胆道损伤后,伴有血管的胆管数量较CON组明显减少,而不伴有血管的胆管数却明显增加(P<0.05); rhGH处理后,伴有血管的胆管数量较ITBL组明显增多,而不伴有血管的胆管数却明显减少(P<0.05)。
第三部分生长激素对肝移植缺血型胆道损伤的保护作用及其机制
目的：探讨外源性生长激素对大鼠肝移植缺血型胆道损伤的保护作用及其机制。
材料与方法
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速采取下腔静脉血液离心取上清液,取左外叶肝组织置于10%多聚甲醛溶液保存。
3.检测指标
(1)血清ALT和ALP检测。
(2)免疫组化法检测胆管上皮细胞VEGF、VEGFR2、VEGFR3、IGF-1R和GHR表达。封片后用Olympus U-25ND6 T2显微镜观察显微结构,用IAS图像分析系统(Delta Sistemi)分析图像,估算免疫组化染色的强度和分布。
(3)胆管上皮细胞的PCNA标记用半定量法测定。在20个随机的高倍视野(-400)计数500个胆管细胞,计算PCNA阳性细胞百分数,由此估算PCNA标记指数。只有表达核免疫染色强阳性的细胞才‘被列入阳性计数。
(4)采用TUNEL法按细胞凋亡检测试剂盒操作说明进行检测,光镜下观察各组大鼠肝内胆管上皮细胞凋亡情况。在高倍视野(×400)下盲法检测每个组织样本中凋亡细胞数。用凋亡指数进行定量,即30个随机显微高倍视野的阳性细胞数来算出TUNEL阳性胆管上皮细胞百分数。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果
1. ITBL组的ALT和ALP显著高于对照组(P<0.05); rhGH组ALT和ALP较ITBL组明显降低(P<0.05),然而仍高于CON组(P<0.05)。
2.免疫组化检测显示,ITBL组肝脏表达VEGF、VEGFR2、VEGFR3、GHR和IGF-1R阳性胆管上皮细胞数较CON组减少(P<0.05); rhGH组阳性表达较ITBL组明显提高(P<0.05),但仍较CON组低(P<0.05)。
3. TUNEL分析显示,CON组大鼠表达少量凋亡细胞,ITBL组大鼠胆管上皮细胞凋亡较CON组增加(P<0.05), rhGH处理抑制ITBL所致的胆管上皮细胞凋亡(P<0.05)。
4. ITBL组PCNA阳性胆管上皮细胞数较对照组减少(P<0.05), rhGH处理解除ITBL对PCNA阳性胆管上皮细胞数的抑制(P<0.05)。
结论：
1.缺血型胆道损伤直接损害胆管上皮细胞,使胆道超微结构破坏,外源性生长激素处理明显减轻肝移植缺血型胆道损伤,对胆道具有保护作用。
2.缺血型胆道损伤使肝内胆道微循环受损,而外源性生长激素促进肝内胆道微循环的恢复从而对胆道有保护作用。
3. rhGH处理明显减轻肝移植肝内缺血型胆道损伤,这可能与rhGH通过提高肝内胆管上皮细胞VEGF、VEGFR-2、VEGFR-3、GHR和IGF1-R表达,从而抑制凋亡、促进增生有关。
The protect of ischemic-type biliary lesion(ITBL) is very important to improve the grafts blood suppuly and achievement ratio of liver transplantation. ITBL is a complicated pathologic progress related with multiple factors, stricture and occlusion of the hepatic artery is the most important causes since the blood supply of the graft comes mainly from the hepatic artery. Rhcombinant human growth hormone can protect tissues against ischemia injury, which can potentiate the protein synthesis of the organism, ameliorate the immunologic function of the organism, depress stress reaction, and activate production of IGF-1. The study was to establish the simple and practical model of rat autologous liver transplantation, and ITBL was made, rhGH was utilized aftertreatment. The ultrastructure and microcirculation of intrahepatic bile ducts, apoptosis and proliferation of cholangiocytes, and correlative controlling gene expression were observed postoperation, sequentially the protective effect of rhGH on ITBL relating to liver transplantaion and its mechanism were evaluated, in order to provide the theory and experimental basis of using rhGH in the field of protection on bile ducts after liver transplantation. At civil and abroad, there is still no written report on this aspect.
Part I:Effects of ITBL on ultrastructure of bile ducts relting to liver transplantation and protection of growth hormone
Objective:RhGH was utilized aftertreatmemt in rats with autologous liver transplantation, thereafter the ultrastructure of bile ducts was observed, sequentially the protective effect of GH on ITBL relating to liver transplantaion and its mechanism were evaluated.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised, some was preserved in 10% paraformaldehyde, some was preserved in 2.5% glutaraldehyde for further test.
3. checking of items
(1) pathological examination The tissue of bile ducts preserved in 10% paraformaldehyde was taken, cropped, and made into wax pattern, thereafter sliced up, dyed with hematoxylin-eosin. Edema of cholangyocytes, infiltration of inflammatory cells, necrosis and exfoliation of cholangyocytes were observed with high power field of microscope.
(2) transmission elctron microscope observation and image analysis The tissue of bile ducts preserved in 2.5% glutaraldehyde was taken and made into specimen. Ultrastructure of cholangyocytes was observed, and the injury levels of the epithelia were analyzed quantitatively in a specialized image analysis system.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. pathologic changes with hematoxylin-eosin dyeing In CON group, the primary injury was reversible, such as edema of cholangyocytes and infiltration of inflammatory cells; In ITBL group, the primary injury was unreversible, such as necrosis and exfoliation of cholangyocytes; In rhGH group, the primary injury was edema of cholangyocytes and infiltration of inflammatory cells, while necrosis and exfoliation of cholangyocytes were remarkably decreased.
2. transmission electron microscope observation In CON group, mucosal folds of bile ducts were full and fluctuant naturally without layer of epithelia broken. Cholangiocytes were roundish or oval, normomorph, homogeneous with regular arrangement. Epithelial microvilli were thick; In ITBL group, the cholangiocytes presented faveolate necrosis with collagenous fibers denuding of substratum. The remnant epithelia were paramorph with bigger septa between each other. Epithelial microvilli were sparse; In rhGH group, the number of cholangiocytes was increased with normomorph, the septa among cholangiocytes were basically well-balanced. Epithelial microvilli were thick but with a little paramorph.
3. image analysis In ITBL group, the epithelial plane measurement parameter, including the density of area and quantity of epithelia, and the density of area of epithelial microvilli, was significantly decreased compared with CON or rhGH group (P<0.05); In rhGH group, the epithelial plane measurement parameter was increased compared with ITBL group (P<0.05), but still decreased compared with CON group (P<0.05).
PartⅡ:Effect of ITBL on microcirculation of bile ducts relating to liver transplantation and protection of growth hormone
Objective:RhGH was utilized aftertreatmemt in rats with autologous liver transplantation, thereafter the microcirculation of bile ducts was observed, sequentially the protective effect of GH on ITBL relating to liver transplantaion and its mechanism were evaluated.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised and preserved in 10% paraformaldehyde thereafter made into wax pattern.
3. checking of items
(1) pathological examination The wax pattern was cut into slices of 2.5μm, dyed with hematoxylin-eosin. The soakage of inflammatory cells in potal areas and breakage of bile ducts were observed.
(2) The wax pattern was cut into slices of 2.5μm continuously. The blood vessels were tagged with rabbit anti-CD34 polyclonal antibody. In portal area, the number of bile ducts, blood vessels, bile ducts accompanying with blood vessels, bile ducts not accompanying with blood vessels, and isolated blood vessels were counted, respectively.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. pathologic changes In ITBL group, the array of intrahepatic cholangiocytes was significantly absent. There was neither incrassated vessel wall of bile ducts, nor obvious soakage of inflammatory cells in portal area; In CON or rhGH group, the changes of chronic hyperplastic inflammation were oberserved in intrahepatic cholangiocytes. There were incrassated vessel wall of bile ducts, increased inflammatory cells in portal area, and hyperplastic cholangiocytes.
2. bile ducts and blood vessels in portal area In ITBL group, the bile ducts in portal area were damaged, and decreased compared with CON group (P<0.05); In rhGH group, the bile ducts in portal area were obviously increased compared with ITBL group (P<0.05). In ITBL group, the number of bile ducts accompanying with blood vessels was significantly decreased, while not accompanying with blood vessels was significantly increased (P<0.05); In rhGH group, the number of bile ducts accompanying with blood vessels was significantly increased, while not accompanying with blood vessels was significantly decreased, compared with ITBL group (P<0.05).
Part III:GH attenuates ITBL of intrahepatic bile ducts relating to liver transplantation and its mechanism
Objectives:To discuss the protective effect of exogenoue GH on ITBL relating to liver transplantaion and its mechanism.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, blood collected from the inferior vena cava was centrifugated for supernate, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised and preserved in 10% paraformaldehyde.
3. checking of items
(1) Alanine aminotransferase (ALT), alkaline phosphatase (ALP) were measured in the serum.
(2) Immunohistochemical examination for VEGF, VEGFR2, VEGFR3, IGF-1R and GHR expressed in cholangiocytes. Following staining, ultrastructure was observed with Olympus U-25ND6 T2 microscope. Images were analyzed with an IAS image analysis system (Delta Sistemi), the intensity and distribution of immunostaining were assessed accordingly.
(3) PCNA labeling of cholangiocytes was semi-quantitatively evaluated by counting at least 500 bile-duct cells in 20 randomly selected high-power fields (×400) and by determining the percentages of PCNA-reactive cells. Thus PCNA labeling index was evaluated. Only bile-duct cells that exhibited stong nuclear immunostaining were considered for reactive cell counting.
(4) Using the TUNEL method refered to the measure kit handling instruction of apoptosis, intrahepatic cholangiocytes apoptosis in rats of each group was observed with light microscope. Apoptotic cells were counted for each tissue sample under high-power magnification (×400) in a blinded fashion. Apoptotic index (AI) was used as a quantitative indicator, indicating the percentage of TUNEL-positive cholangiocytes by counting the number of positive cells in 30 random microscopic high-power fields.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. The ALT and ALP of ITBL group were significantly higher compared with CON group (P<0.05); The ALT and ALP of rhGH group were significantly decreased compared with ITBL group (P<0.05), but still higher compared with CON group (P<0.05).
2. It was showed by immunohistochemistry checking that, ITBL induced a decrease in the number of intrahepatic cholangicyte positive for VEGF, VEGFR2, VEGFR3, GHR and IGF-1R compared with CON rats(P<0.05); In rhGH rats, the expression of VEGF, VEGFR2, VEGFR3, GHR and IGF-1R was significantly higher compared with ITBL animals (P<0.05), but however, remained lower when compared with CON group(P<0.05).
3. TUNEL analysis showed a few apoptotic bodies in the liver sections of CON rats. The number of cholangiocytes undergoing apoptosis increased in liver sections from ITBL rats compared with CON rats (P<0.05). Administration of rhGH prevented the increase in cholangiocytes apoptosis induced by ITBL (P<0.05).
4. Following ITBL, the number of PCNA-positive cholangiocytes decreased compared with liver sections from CON rats (P<0.05). Administration of rhGH prevented the inhibitory effect of ITBL on the number of PCNA-positive cholangiocytes(P<0.05).
Conclusions:
1. ITBL can directly damnify the epithelia of bile ducts, destroy the ultrastruture of bile ducts; Administration of rhGH can significantly alleviate ITBL relating to liver transplantation, threreafter protect bile ducts from ITBL.
2. ITBL relating to rat orthotopic autologous liver transplantation damnifies the microcirculation of intrahepatic bile ducts. Administration of exogenous GH promotes recovery of intrahepatic microcirculation consequently protecting bile ducts from ITBL.
3. Administration of rhGH appears to attenuate ITBL of intrahepatic bile ducts relating to liver transplantation. This function is partly related with the capacity that rhGH inhibits the apoptosis of intrahepatic cholangiocytes and prompts the proliferation, by increasing the expression of VEGF, VEGFR2, VEGFR3, GHR and IGF1-R.
第一部分缺血型胆道损伤对肝移植胆道超微结构的影响及生长激素的保护作用
目的：应用重组人生长激素,对大鼠自体原位肝移植术后缺血型胆道损伤进行术后干预,观察胆道超微结构改变,探讨生长激素对肝移植缺血型胆道损伤的保护作用与机制。
材料与方法：
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速获取左肝外叶胆道组织,部分置于10%多聚甲醛溶液以备光镜检查,部分置于2.5%戊二醛固定液中以备透射电镜分析。
3.检测指标
(1)胆道组织病理检测取上述10%多聚甲醛所固定组织,稍加修整,制成组织蜡块、切片,常规HE染色。高倍镜视野下,观察胆管上皮水肿、炎细胞浸润、上皮坏死脱落等情况。
(2)胆道透射电镜观察及图像分析取上述2.5%戊二醛所固定组织,制成电镜标本,电镜观察各组胆管上皮微观结构改变,并用图像分析系统对其损伤程度进行定量分析。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果
1.胆管组织学变化HE染色显示,CON组以胆管上皮水肿、炎细胞浸润等可逆性损伤为主；ITBL组以上皮大部分坏死脱落等不可逆损伤为主；而rhGH组,胆道上皮坏死脱落明显减少,以胆管上皮水肿、炎细胞浸润为主。
2.透射电镜观察术后1周CON组可见胆管的粘膜皱褶饱满,起伏自然,无上皮层破损,胆管上皮细胞呈圆形或椭圆形,形态规则,大小均一,排列整齐,表面微绒毛较丰富；ITBL组可见胆管上皮细胞呈蜂窝状坏死,基层胶原纤维裸露,残余上皮细胞欠规则,间距较大,表面微绒毛稀疏；rhGH组可见细胞数量增多,形态基本正常,细胞间距基本正常,表面微绒毛丰富但形态欠均匀。
3.胆管上皮透射电镜图像分析ITBL组的胆管上皮细胞面积密度、数密度和微绒毛面积密度等平面计量学参数均显著小于CON组和rhGH组(P<0.05)；rhGH组的胆管上皮细胞平面计量学参数较ITBL组有明显改善(P<0.05),但仍较CON组低(P<0.05)。
第二部分缺血型胆道损伤对肝移植胆道微循环的影响及生长激素的保护作用
目的：应用重组人生长激素,对大鼠自体原位肝移植术后缺血型胆道损伤进行术后干预,观察肝内胆道微循环变化,探讨生长激素对肝移植缺血型胆道损伤的保护作用与机制。
材料与方法：
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速获取左肝外叶胆道组织,置于10%多聚甲醛溶液以备石蜡切片。
3.检测指标
(1)病理学检查：石蜡标本2.5μm切片,常规HE染色。观察汇管区炎症细胞浸润及胆管结构破坏程度。
(2)石蜡标本2.5μm连续切片,用兔抗CD34多克隆抗体标记血管。计数汇管区胆管数、血管数、伴有血管的胆管数、不伴有血管的胆管数及孤立的血管数。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果1.胆管病理形态观察ITBL组胆管上皮细胞排列明显缺失,管壁无增厚,汇管区也无明显炎症细胞浸润。CON组、rhGH组胆管上皮细胞呈慢性增生性炎症改变,管壁明显增厚,汇管区炎性细胞增多,胆管上皮细胞增生2.汇管区胆管及血管的变化胆道缺血性损伤后,汇管区胆管受损,ITBL组较CON组汇管区胆管数明显减少(P<0.05); rhGH处理后,汇管区胆管增生,rhGH组较ITBL组汇管区胆管数明显增加(P<0.05)。缺血型胆道损伤后,伴有血管的胆管数量较CON组明显减少,而不伴有血管的胆管数却明显增加(P<0.05); rhGH处理后,伴有血管的胆管数量较ITBL组明显增多,而不伴有血管的胆管数却明显减少(P<0.05)。
第三部分生长激素对肝移植缺血型胆道损伤的保护作用及其机制
目的：探讨外源性生长激素对大鼠肝移植缺血型胆道损伤的保护作用及其机制。
材料与方法
1.动物分组与模型制备
选用wistar系雄性大鼠18只,体重200±20g,随机分为3组：对照组(CON组)、缺血型胆道损伤组(ITBL组)和rhGH处理组(rhGH组),每组6只。CON组仅进行自体原位肝移植；rhGH组于术后3h结扎肝动脉,并且皮下注射rhGH 0.3IU/kg/天共一周；ITBL组于术后3h结扎肝动脉,并且皮下注射等量生理盐水一周。
2.标本的采集与处理
术后7天再次开腹,快速采取下腔静脉血液离心取上清液,取左外叶肝组织置于10%多聚甲醛溶液保存。
3.检测指标
(1)血清ALT和ALP检测。
(2)免疫组化法检测胆管上皮细胞VEGF、VEGFR2、VEGFR3、IGF-1R和GHR表达。封片后用Olympus U-25ND6 T2显微镜观察显微结构,用IAS图像分析系统(Delta Sistemi)分析图像,估算免疫组化染色的强度和分布。
(3)胆管上皮细胞的PCNA标记用半定量法测定。在20个随机的高倍视野(-400)计数500个胆管细胞,计算PCNA阳性细胞百分数,由此估算PCNA标记指数。只有表达核免疫染色强阳性的细胞才‘被列入阳性计数。
(4)采用TUNEL法按细胞凋亡检测试剂盒操作说明进行检测,光镜下观察各组大鼠肝内胆管上皮细胞凋亡情况。在高倍视野(×400)下盲法检测每个组织样本中凋亡细胞数。用凋亡指数进行定量,即30个随机显微高倍视野的阳性细胞数来算出TUNEL阳性胆管上皮细胞百分数。
4.统计分析：全部数据均由SPSS13.0软件进行统计学处理。多组间比较用方差分析(ANOVA),随后用合适的方法作多重比较。数据结果采用均数±标准差表示,P<0.05为差异有统计学意义。
结果
1. ITBL组的ALT和ALP显著高于对照组(P<0.05); rhGH组ALT和ALP较ITBL组明显降低(P<0.05),然而仍高于CON组(P<0.05)。
2.免疫组化检测显示,ITBL组肝脏表达VEGF、VEGFR2、VEGFR3、GHR和IGF-1R阳性胆管上皮细胞数较CON组减少(P<0.05); rhGH组阳性表达较ITBL组明显提高(P<0.05),但仍较CON组低(P<0.05)。
3. TUNEL分析显示,CON组大鼠表达少量凋亡细胞,ITBL组大鼠胆管上皮细胞凋亡较CON组增加(P<0.05), rhGH处理抑制ITBL所致的胆管上皮细胞凋亡(P<0.05)。
4. ITBL组PCNA阳性胆管上皮细胞数较对照组减少(P<0.05), rhGH处理解除ITBL对PCNA阳性胆管上皮细胞数的抑制(P<0.05)。
结论：
1.缺血型胆道损伤直接损害胆管上皮细胞,使胆道超微结构破坏,外源性生长激素处理明显减轻肝移植缺血型胆道损伤,对胆道具有保护作用。
2.缺血型胆道损伤使肝内胆道微循环受损,而外源性生长激素促进肝内胆道微循环的恢复从而对胆道有保护作用。
3. rhGH处理明显减轻肝移植肝内缺血型胆道损伤,这可能与rhGH通过提高肝内胆管上皮细胞VEGF、VEGFR-2、VEGFR-3、GHR和IGF1-R表达,从而抑制凋亡、促进增生有关。
The protect of ischemic-type biliary lesion(ITBL) is very important to improve the grafts blood suppuly and achievement ratio of liver transplantation. ITBL is a complicated pathologic progress related with multiple factors, stricture and occlusion of the hepatic artery is the most important causes since the blood supply of the graft comes mainly from the hepatic artery. Rhcombinant human growth hormone can protect tissues against ischemia injury, which can potentiate the protein synthesis of the organism, ameliorate the immunologic function of the organism, depress stress reaction, and activate production of IGF-1. The study was to establish the simple and practical model of rat autologous liver transplantation, and ITBL was made, rhGH was utilized aftertreatment. The ultrastructure and microcirculation of intrahepatic bile ducts, apoptosis and proliferation of cholangiocytes, and correlative controlling gene expression were observed postoperation, sequentially the protective effect of rhGH on ITBL relating to liver transplantaion and its mechanism were evaluated, in order to provide the theory and experimental basis of using rhGH in the field of protection on bile ducts after liver transplantation. At civil and abroad, there is still no written report on this aspect.
Part I:Effects of ITBL on ultrastructure of bile ducts relting to liver transplantation and protection of growth hormone
Objective:RhGH was utilized aftertreatmemt in rats with autologous liver transplantation, thereafter the ultrastructure of bile ducts was observed, sequentially the protective effect of GH on ITBL relating to liver transplantaion and its mechanism were evaluated.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised, some was preserved in 10% paraformaldehyde, some was preserved in 2.5% glutaraldehyde for further test.
3. checking of items
(1) pathological examination The tissue of bile ducts preserved in 10% paraformaldehyde was taken, cropped, and made into wax pattern, thereafter sliced up, dyed with hematoxylin-eosin. Edema of cholangyocytes, infiltration of inflammatory cells, necrosis and exfoliation of cholangyocytes were observed with high power field of microscope.
(2) transmission elctron microscope observation and image analysis The tissue of bile ducts preserved in 2.5% glutaraldehyde was taken and made into specimen. Ultrastructure of cholangyocytes was observed, and the injury levels of the epithelia were analyzed quantitatively in a specialized image analysis system.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. pathologic changes with hematoxylin-eosin dyeing In CON group, the primary injury was reversible, such as edema of cholangyocytes and infiltration of inflammatory cells; In ITBL group, the primary injury was unreversible, such as necrosis and exfoliation of cholangyocytes; In rhGH group, the primary injury was edema of cholangyocytes and infiltration of inflammatory cells, while necrosis and exfoliation of cholangyocytes were remarkably decreased.
2. transmission electron microscope observation In CON group, mucosal folds of bile ducts were full and fluctuant naturally without layer of epithelia broken. Cholangiocytes were roundish or oval, normomorph, homogeneous with regular arrangement. Epithelial microvilli were thick; In ITBL group, the cholangiocytes presented faveolate necrosis with collagenous fibers denuding of substratum. The remnant epithelia were paramorph with bigger septa between each other. Epithelial microvilli were sparse; In rhGH group, the number of cholangiocytes was increased with normomorph, the septa among cholangiocytes were basically well-balanced. Epithelial microvilli were thick but with a little paramorph.
3. image analysis In ITBL group, the epithelial plane measurement parameter, including the density of area and quantity of epithelia, and the density of area of epithelial microvilli, was significantly decreased compared with CON or rhGH group (P<0.05); In rhGH group, the epithelial plane measurement parameter was increased compared with ITBL group (P<0.05), but still decreased compared with CON group (P<0.05).
PartⅡ:Effect of ITBL on microcirculation of bile ducts relating to liver transplantation and protection of growth hormone
Objective:RhGH was utilized aftertreatmemt in rats with autologous liver transplantation, thereafter the microcirculation of bile ducts was observed, sequentially the protective effect of GH on ITBL relating to liver transplantaion and its mechanism were evaluated.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised and preserved in 10% paraformaldehyde thereafter made into wax pattern.
3. checking of items
(1) pathological examination The wax pattern was cut into slices of 2.5μm, dyed with hematoxylin-eosin. The soakage of inflammatory cells in potal areas and breakage of bile ducts were observed.
(2) The wax pattern was cut into slices of 2.5μm continuously. The blood vessels were tagged with rabbit anti-CD34 polyclonal antibody. In portal area, the number of bile ducts, blood vessels, bile ducts accompanying with blood vessels, bile ducts not accompanying with blood vessels, and isolated blood vessels were counted, respectively.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. pathologic changes In ITBL group, the array of intrahepatic cholangiocytes was significantly absent. There was neither incrassated vessel wall of bile ducts, nor obvious soakage of inflammatory cells in portal area; In CON or rhGH group, the changes of chronic hyperplastic inflammation were oberserved in intrahepatic cholangiocytes. There were incrassated vessel wall of bile ducts, increased inflammatory cells in portal area, and hyperplastic cholangiocytes.
2. bile ducts and blood vessels in portal area In ITBL group, the bile ducts in portal area were damaged, and decreased compared with CON group (P<0.05); In rhGH group, the bile ducts in portal area were obviously increased compared with ITBL group (P<0.05). In ITBL group, the number of bile ducts accompanying with blood vessels was significantly decreased, while not accompanying with blood vessels was significantly increased (P<0.05); In rhGH group, the number of bile ducts accompanying with blood vessels was significantly increased, while not accompanying with blood vessels was significantly decreased, compared with ITBL group (P<0.05).
Part III:GH attenuates ITBL of intrahepatic bile ducts relating to liver transplantation and its mechanism
Objectives:To discuss the protective effect of exogenoue GH on ITBL relating to liver transplantaion and its mechanism.
Material and methods:
1. experimental groups and model establishment
Adult male wistar rats weighing 200±20g were choosed and randomly divided into three groups each with 6 rats including:control group(CON group), in which the animals had the relevant operation without hepatic artery ligation; ITBL group, in which the hepatic artery was ligated after the operation, subsequently 0.3ml/kg/d water for injection had been administered subcutaneously for 1 week; and rhGH group, in which the hepatic artery was ligated after the operation, subsequently rhGH had been administered subcutaneously 0.3IU/kg diluted in 0.3ml water for injection for 1 week.
2. specimen collection and disposal
The rats underwent relaparotomy 7 days postoperation, blood collected from the inferior vena cava was centrifugated for supernate, the tissue of bile ducts from the hepatic left lateral lobe was rapidly excised and preserved in 10% paraformaldehyde.
3. checking of items
(1) Alanine aminotransferase (ALT), alkaline phosphatase (ALP) were measured in the serum.
(2) Immunohistochemical examination for VEGF, VEGFR2, VEGFR3, IGF-1R and GHR expressed in cholangiocytes. Following staining, ultrastructure was observed with Olympus U-25ND6 T2 microscope. Images were analyzed with an IAS image analysis system (Delta Sistemi), the intensity and distribution of immunostaining were assessed accordingly.
(3) PCNA labeling of cholangiocytes was semi-quantitatively evaluated by counting at least 500 bile-duct cells in 20 randomly selected high-power fields (×400) and by determining the percentages of PCNA-reactive cells. Thus PCNA labeling index was evaluated. Only bile-duct cells that exhibited stong nuclear immunostaining were considered for reactive cell counting.
(4) Using the TUNEL method refered to the measure kit handling instruction of apoptosis, intrahepatic cholangiocytes apoptosis in rats of each group was observed with light microscope. Apoptotic cells were counted for each tissue sample under high-power magnification (×400) in a blinded fashion. Apoptotic index (AI) was used as a quantitative indicator, indicating the percentage of TUNEL-positive cholangiocytes by counting the number of positive cells in 30 random microscopic high-power fields.
4. statistical analysis All the data were analyzed by software SPSS 13.0. Defference between groups were analyzed by analysis of variance (ANOVA) when more than two groups were analyzed, followed by an appropiate post hoc test. All data were expressed as mean value±standard deviation, P-values of less than 0.05 were accepted as statistically significant.
Results:
1. The ALT and ALP of ITBL group were significantly higher compared with CON group (P<0.05); The ALT and ALP of rhGH group were significantly decreased compared with ITBL group (P<0.05), but still higher compared with CON group (P<0.05).
2. It was showed by immunohistochemistry checking that, ITBL induced a decrease in the number of intrahepatic cholangicyte positive for VEGF, VEGFR2, VEGFR3, GHR and IGF-1R compared with CON rats(P<0.05); In rhGH rats, the expression of VEGF, VEGFR2, VEGFR3, GHR and IGF-1R was significantly higher compared with ITBL animals (P<0.05), but however, remained lower when compared with CON group(P<0.05).
3. TUNEL analysis showed a few apoptotic bodies in the liver sections of CON rats. The number of cholangiocytes undergoing apoptosis increased in liver sections from ITBL rats compared with CON rats (P<0.05). Administration of rhGH prevented the increase in cholangiocytes apoptosis induced by ITBL (P<0.05).
4. Following ITBL, the number of PCNA-positive cholangiocytes decreased compared with liver sections from CON rats (P<0.05). Administration of rhGH prevented the inhibitory effect of ITBL on the number of PCNA-positive cholangiocytes(P<0.05).
Conclusions:
1. ITBL can directly damnify the epithelia of bile ducts, destroy the ultrastruture of bile ducts; Administration of rhGH can significantly alleviate ITBL relating to liver transplantation, threreafter protect bile ducts from ITBL.
2. ITBL relating to rat orthotopic autologous liver transplantation damnifies the microcirculation of intrahepatic bile ducts. Administration of exogenous GH promotes recovery of intrahepatic microcirculation consequently protecting bile ducts from ITBL.
3. Administration of rhGH appears to attenuate ITBL of intrahepatic bile ducts relating to liver transplantation. This function is partly related with the capacity that rhGH inhibits the apoptosis of intrahepatic cholangiocytes and prompts the proliferation, by increasing the expression of VEGF, VEGFR2, VEGFR3, GHR and IGF1-R.
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