肝脏卵圆细胞在急性胆道梗阻中变化的研究
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摘要
一、背景和目的
现已发现人慢性肝病组织如肝硬化、亚大块肝坏死后肝再生、儿童先天性肝外胆道闭锁、遗传性血色病、慢性病毒性肝炎、原发性肝癌中都存在类似于卵圆细胞的肝前体细胞。这种肝前体细胞定位于汇管区、纤维间隔、汇管区旁肝实质、假小叶及炎症边界。研究发现卵圆细胞存在于肝硬化,肝癌等各种慢性肝病的肝脏组织中,肝脏卵圆细胞在慢性肝炎肝脏组织中阳性表达。随着肝脏卵圆细胞特异性标记物的发现,卵圆细胞相关研究成为热点,特别是肝脏卵圆细胞双重分化特性及参加肝脏损伤后的修复的相关研究,更为研究者探究肝脏损伤的保护、治疗及肝纤维化的形成机制提供了最新途径。
在肝胆外科临床中,胆道梗阻、胆汁淤积是常见的病理环境,较长时间梗阻,可诱发永久性肝损害,甚至发展成肝纤维化及肝硬化,是临床治疗的难题,相关发病机制基础研究有现实意义。目前肝脏卵圆细胞与外科急性胆道梗阻后肝组织损伤及修复的相关研究,国内外鲜见报道。另外,胆道梗阻模型可以结扎啮齿类动物的胆总管获得,大鼠的胆总管结扎模型已有了评估和描述,为研究提供了可靠的动物模型。
本研究通过结扎Wistar大鼠胆总管动物模型,复制急性胆道梗阻病理状态,评估胆总管结扎模型的可行性并总结模型建立经验；通过组织学技术,探究肝脏卵圆细胞与急性胆道梗阻后肝脏病理改变的相关性。
二、材料与方法
雄性Wistar大鼠90只。体重250-300克,将动物随机分成实验组和对照组。每组每个时间点通过胆总管接扎,造模成功8只。术后观察所有动物的体重、活动及黄疸情况。术后第1、2、3、5、7天,每组各处死8只,取血行总胆红素(TBIL)、直胆红素(DBIL)、谷丙转氨酶(ALT)、碱性磷酸酶(ALP)检查。取肝右叶应用4%多聚甲醛固定,行肝脏组织学分析。
1、通过观察不同时间点实验动物的体重、黄疸及活动变化情况,采集不同时间点血液标本,进行酶学检测,总结模型死亡率和成功率。
2、绘制不同时间点实验动物体重、酶学指标变化曲线,总结其与病情、病程之间的相关性。
3、通过肉眼及HE染色观察急性胆道梗阻不同时间点肝脏形态改变。
4、通过胶原特殊染色,观察肝脏胶原增生情况。
5、通过免疫组化,OV-6标记卵圆细胞,观察不同时间点卵圆细胞的数目、分布,探究其与急性胆道梗阻的关系及变化规律。
三、结果
预实验中未分离胆管及结扎胆管位置过高,出现动物死亡和模型成功率仅40%。改进后实验组造模成功率达90%。实验组大鼠术后第1天有体重显著减轻,但此后体重稳定升高,但体重均低于实验对照组。术后2天内活动显著减少,第3天后基本恢复正常,而假手术动物活力无明显变化。实验组动物自第1天出现黄疸,于术后第3天黄疸加重。对照组有一只出现黄疸,从组中剔除。胆总管结扎(bile duct ligation, BDL)后TBIL和DBIL两组有显著差异(P<0.001)。ALT迅速增加,高峰在术后第1-2天,第3天后迅速下降。ALP术后第2天达到高峰,第3天后稳步增加。
急性胆道梗阻后,肝组织学检查显示：梗阻时间延长,肝细胞发生变性坏死程度加重,伴有大量以中性粒细胞为主的炎性细胞浸润,从胆管梗阻处逐渐转向肝门。胶原染色特异性显示胶原纤维为红色,显微镜下观察胶原纤维分布与含量两组术后第1及2天无明显差异,而术后第3、5、7天两组的胶原含量及分布范围有明显差异。实验组肝脏胶原纤维梗阻时间延长则增生明显。
OV-6免疫组化阳性染色的细胞数目及分布范围随着梗阻时间的延长而增加,实验组和对照组有明显差异。(P<0.05)
四、结论
1、按照本实验描述的模型建立方法,简单易行、重复性及稳定性好,可以得到满意急性胆道梗阻模型。造模成功率与分离胆管的精确度、结扎位置、力度、胆管侧枝存在及动物个体差异性相关。
2、急性胆道梗阻后肝脏细胞损伤逐渐加重,胆道梗阻后第3天,是肝脏细胞急性损伤反应最强烈的时间点,之后机体开始进入自我调节及修复过程。胆道梗阻后7天,激活了具有分化能力的储备细胞,修复过程伴随着肝细胞间的纤维组织增生,出现纤维化,但未发现典型的肝脏假小叶形成。
3、本实验发现卵圆细胞参与肝细胞在急性胆道梗阻后损伤的修复过程。肝卵圆细胞不仅是参与肝损伤修复的主导细胞,也是肝组织内对进行性受损反应最敏感的一种细胞。受损的肝脏中卵圆细胞的增生规律与胶原纤维增生具有相似性。
Background and Objective
The liver progenitor cells,oval cells, has been found in the chronic liver disease such as cirrhosis of the liver, sub-massive hepatic necrosis of liver regeneration, children with congenital extrahepatic biliary atresia, hereditary hemochromatosis, chronic viral hepatitis, hepatocellular carcinoma. This hepatic progenitor cells located in periportal areas, fiber spacing, periportal zone adjacent hepatic parenchyma, and inflammatory pseudo-lobular borders. Study found that oval cells exist in liver cirrhosis, liver cancer and other chronic liver disease positive expression of liver tissue. With the specific markers of the oval cells found, research about oval cells has been hot,especially in the dual differentiation of oval cells and take part in the repair of liver injury,but even more researchers to explore is the provision of liver injure and liver fibrosis.However, in the liver and gallbladder surgery clinical biliary obstruction, cholestasis is a common pathological states, clinical treatment is ineffective, related to the pathogenesis of basic research has practical significance. Currently oval cells of liver after biliary obstruction and surgical tissue injury and repair-related research, rare reports at home and abroad. And biliary obstruction model of the common bile duct ligation and rodents obtained the common bile duct ligation model in rats has been evaluated and described for the study provides a reliable animal model. In this study,Wistar rats by common bile duct ligation animal model, replication of acute biliary obstruction pathological states, evaluate the feasibility of common bile duct ligation model and summarizes the model building experience; by histological techniques, explore the relation of oval cells and bile duct obstruction in acute pathological states.
Methods:
Male Wistar rat 90.Body weight 250-300g, were randomly divided into experimental group and control group. Each group modeling success 8 through the common bile duct ligation at each time point. Observed after the weight of all animals, activities and Jaundice. The1,2,3,5,7 day after the operation, eight in each group were sacrificed to make total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), alkaline phosphatase (ALP) examination. Take right lobe of liver 4% paraformaldehyde fixed histological analysis.
1 looking the weight of experimental animals, jaundice and activity changes at different time points, collecting the blood samples at different time points to carry out enzymatic detection, sum up model mortality and success rate.
2 drawing experimental animals at different time points, body weight, enzyme indicators of change curve, summed up with the disease, the correlation between course of disease.
3 through the naked eye, and HE staining of bile duct obstruction in acute liver morphological changes at different time points.
4 by collagen specific staining of collagen proliferation in the liver.
5 by immunohistochemistry, OV-6 marker of oval cells, to observe the number and distribution of oval cellsat different time points, to explore its relationship with acute biliary obstruction and the rule of changes.
Results
Pre-experiment, non-separating bile duct and bile duct ligation too high that induce animal death and the model success rate only 40%. Modeling improved, the success rate of the model in the experimental group increases to 90%.
Experimental rats after 1 days significantly reduced body weight, but since then a stable body weight increased, but body weight were lower than the experimental control group. After 2 days, a marked reduction in the first three days later returned to normal, while the sham-operated animals, no significant change in activity. Experimental animals with jaundice occurring since day 1, was increased after the first 3 days of jaundice. The control group had a jaundice, from the group removed. TBIL and DBIL after BDL groups were significantly different (P<0.001). ALT increased rapidly after the peak in the first 1-2 days,3 days later to decline rapidly. ALP after the first two days to reach the peak, the first three days after increasing steadily.
Acute biliary obstruction on liver histological examination showed prolonged obstruction, degree of degeneration and necrosis of liver cells increased, accompanied by large amounts of neutrophil-based inflammatory cell infiltration, bile duct obstruction, gradually shifted from the portal.
Collagen-specific staining showed collagen fibers red, collagen fibers observed under the microscope distribution and content of the two groups 1 and 2 days after the first was no significant differences in the two days after the first 3,5,7 and distribution of collagen content in the scope of significant difference. Hepatic collagen fibers in the experimental group were prolonged obstruction with marked hyperplasia.
OV-6 positive immunohistochemical staining of cells with the obstruction of the number and distribution of the extension of time to increase the experimental group and control group were different significantly. (P<0.05)
Conclusions
1 The bile duct ligation model described in this study method is simple, reproducible and stable, can be satisfied with acute biliary obstruction model. The success rate of modeling was associated with accuracy and separation of bile duct ligation position, intensity, presence of bile duct branches and animal-related individual differences.
2 Acute liver cell injury after bile duct obstruction gradually worsened, the third day after biliary obstruction, is the strongest point in time in acute liver cell damage response, then the organism entered the self-regulation and the repair process.7 days after biliary obstruction, activation with differentiation of reserve cells, the repair process of liver cells accompanied by fibrous tissue proliferation, fibrosis occurs, but not found in typical false liver lobule formation.
3 It was found that oval cells involved in liver cell injury in acute biliary obstruction in the repair process.Hepatic oval cells in liver tissue is not only on the most sensitive sexual impairment of a cell, is also involved in the leading cells of liver damage repair. The oval cell proliferation and collagen fiber proliferation was similar in damaged liver.
现已发现人慢性肝病组织如肝硬化、亚大块肝坏死后肝再生、儿童先天性肝外胆道闭锁、遗传性血色病、慢性病毒性肝炎、原发性肝癌中都存在类似于卵圆细胞的肝前体细胞。这种肝前体细胞定位于汇管区、纤维间隔、汇管区旁肝实质、假小叶及炎症边界。研究发现卵圆细胞存在于肝硬化,肝癌等各种慢性肝病的肝脏组织中,肝脏卵圆细胞在慢性肝炎肝脏组织中阳性表达。随着肝脏卵圆细胞特异性标记物的发现,卵圆细胞相关研究成为热点,特别是肝脏卵圆细胞双重分化特性及参加肝脏损伤后的修复的相关研究,更为研究者探究肝脏损伤的保护、治疗及肝纤维化的形成机制提供了最新途径。
在肝胆外科临床中,胆道梗阻、胆汁淤积是常见的病理环境,较长时间梗阻,可诱发永久性肝损害,甚至发展成肝纤维化及肝硬化,是临床治疗的难题,相关发病机制基础研究有现实意义。目前肝脏卵圆细胞与外科急性胆道梗阻后肝组织损伤及修复的相关研究,国内外鲜见报道。另外,胆道梗阻模型可以结扎啮齿类动物的胆总管获得,大鼠的胆总管结扎模型已有了评估和描述,为研究提供了可靠的动物模型。
本研究通过结扎Wistar大鼠胆总管动物模型,复制急性胆道梗阻病理状态,评估胆总管结扎模型的可行性并总结模型建立经验；通过组织学技术,探究肝脏卵圆细胞与急性胆道梗阻后肝脏病理改变的相关性。
二、材料与方法
雄性Wistar大鼠90只。体重250-300克,将动物随机分成实验组和对照组。每组每个时间点通过胆总管接扎,造模成功8只。术后观察所有动物的体重、活动及黄疸情况。术后第1、2、3、5、7天,每组各处死8只,取血行总胆红素(TBIL)、直胆红素(DBIL)、谷丙转氨酶(ALT)、碱性磷酸酶(ALP)检查。取肝右叶应用4%多聚甲醛固定,行肝脏组织学分析。
1、通过观察不同时间点实验动物的体重、黄疸及活动变化情况,采集不同时间点血液标本,进行酶学检测,总结模型死亡率和成功率。
2、绘制不同时间点实验动物体重、酶学指标变化曲线,总结其与病情、病程之间的相关性。
3、通过肉眼及HE染色观察急性胆道梗阻不同时间点肝脏形态改变。
4、通过胶原特殊染色,观察肝脏胶原增生情况。
5、通过免疫组化,OV-6标记卵圆细胞,观察不同时间点卵圆细胞的数目、分布,探究其与急性胆道梗阻的关系及变化规律。
三、结果
预实验中未分离胆管及结扎胆管位置过高,出现动物死亡和模型成功率仅40%。改进后实验组造模成功率达90%。实验组大鼠术后第1天有体重显著减轻,但此后体重稳定升高,但体重均低于实验对照组。术后2天内活动显著减少,第3天后基本恢复正常,而假手术动物活力无明显变化。实验组动物自第1天出现黄疸,于术后第3天黄疸加重。对照组有一只出现黄疸,从组中剔除。胆总管结扎(bile duct ligation, BDL)后TBIL和DBIL两组有显著差异(P<0.001)。ALT迅速增加,高峰在术后第1-2天,第3天后迅速下降。ALP术后第2天达到高峰,第3天后稳步增加。
急性胆道梗阻后,肝组织学检查显示：梗阻时间延长,肝细胞发生变性坏死程度加重,伴有大量以中性粒细胞为主的炎性细胞浸润,从胆管梗阻处逐渐转向肝门。胶原染色特异性显示胶原纤维为红色,显微镜下观察胶原纤维分布与含量两组术后第1及2天无明显差异,而术后第3、5、7天两组的胶原含量及分布范围有明显差异。实验组肝脏胶原纤维梗阻时间延长则增生明显。
OV-6免疫组化阳性染色的细胞数目及分布范围随着梗阻时间的延长而增加,实验组和对照组有明显差异。(P<0.05)
四、结论
1、按照本实验描述的模型建立方法,简单易行、重复性及稳定性好,可以得到满意急性胆道梗阻模型。造模成功率与分离胆管的精确度、结扎位置、力度、胆管侧枝存在及动物个体差异性相关。
2、急性胆道梗阻后肝脏细胞损伤逐渐加重,胆道梗阻后第3天,是肝脏细胞急性损伤反应最强烈的时间点,之后机体开始进入自我调节及修复过程。胆道梗阻后7天,激活了具有分化能力的储备细胞,修复过程伴随着肝细胞间的纤维组织增生,出现纤维化,但未发现典型的肝脏假小叶形成。
3、本实验发现卵圆细胞参与肝细胞在急性胆道梗阻后损伤的修复过程。肝卵圆细胞不仅是参与肝损伤修复的主导细胞,也是肝组织内对进行性受损反应最敏感的一种细胞。受损的肝脏中卵圆细胞的增生规律与胶原纤维增生具有相似性。
Background and Objective
The liver progenitor cells,oval cells, has been found in the chronic liver disease such as cirrhosis of the liver, sub-massive hepatic necrosis of liver regeneration, children with congenital extrahepatic biliary atresia, hereditary hemochromatosis, chronic viral hepatitis, hepatocellular carcinoma. This hepatic progenitor cells located in periportal areas, fiber spacing, periportal zone adjacent hepatic parenchyma, and inflammatory pseudo-lobular borders. Study found that oval cells exist in liver cirrhosis, liver cancer and other chronic liver disease positive expression of liver tissue. With the specific markers of the oval cells found, research about oval cells has been hot,especially in the dual differentiation of oval cells and take part in the repair of liver injury,but even more researchers to explore is the provision of liver injure and liver fibrosis.However, in the liver and gallbladder surgery clinical biliary obstruction, cholestasis is a common pathological states, clinical treatment is ineffective, related to the pathogenesis of basic research has practical significance. Currently oval cells of liver after biliary obstruction and surgical tissue injury and repair-related research, rare reports at home and abroad. And biliary obstruction model of the common bile duct ligation and rodents obtained the common bile duct ligation model in rats has been evaluated and described for the study provides a reliable animal model. In this study,Wistar rats by common bile duct ligation animal model, replication of acute biliary obstruction pathological states, evaluate the feasibility of common bile duct ligation model and summarizes the model building experience; by histological techniques, explore the relation of oval cells and bile duct obstruction in acute pathological states.
Methods:
Male Wistar rat 90.Body weight 250-300g, were randomly divided into experimental group and control group. Each group modeling success 8 through the common bile duct ligation at each time point. Observed after the weight of all animals, activities and Jaundice. The1,2,3,5,7 day after the operation, eight in each group were sacrificed to make total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), alkaline phosphatase (ALP) examination. Take right lobe of liver 4% paraformaldehyde fixed histological analysis.
1 looking the weight of experimental animals, jaundice and activity changes at different time points, collecting the blood samples at different time points to carry out enzymatic detection, sum up model mortality and success rate.
2 drawing experimental animals at different time points, body weight, enzyme indicators of change curve, summed up with the disease, the correlation between course of disease.
3 through the naked eye, and HE staining of bile duct obstruction in acute liver morphological changes at different time points.
4 by collagen specific staining of collagen proliferation in the liver.
5 by immunohistochemistry, OV-6 marker of oval cells, to observe the number and distribution of oval cellsat different time points, to explore its relationship with acute biliary obstruction and the rule of changes.
Results
Pre-experiment, non-separating bile duct and bile duct ligation too high that induce animal death and the model success rate only 40%. Modeling improved, the success rate of the model in the experimental group increases to 90%.
Experimental rats after 1 days significantly reduced body weight, but since then a stable body weight increased, but body weight were lower than the experimental control group. After 2 days, a marked reduction in the first three days later returned to normal, while the sham-operated animals, no significant change in activity. Experimental animals with jaundice occurring since day 1, was increased after the first 3 days of jaundice. The control group had a jaundice, from the group removed. TBIL and DBIL after BDL groups were significantly different (P<0.001). ALT increased rapidly after the peak in the first 1-2 days,3 days later to decline rapidly. ALP after the first two days to reach the peak, the first three days after increasing steadily.
Acute biliary obstruction on liver histological examination showed prolonged obstruction, degree of degeneration and necrosis of liver cells increased, accompanied by large amounts of neutrophil-based inflammatory cell infiltration, bile duct obstruction, gradually shifted from the portal.
Collagen-specific staining showed collagen fibers red, collagen fibers observed under the microscope distribution and content of the two groups 1 and 2 days after the first was no significant differences in the two days after the first 3,5,7 and distribution of collagen content in the scope of significant difference. Hepatic collagen fibers in the experimental group were prolonged obstruction with marked hyperplasia.
OV-6 positive immunohistochemical staining of cells with the obstruction of the number and distribution of the extension of time to increase the experimental group and control group were different significantly. (P<0.05)
Conclusions
1 The bile duct ligation model described in this study method is simple, reproducible and stable, can be satisfied with acute biliary obstruction model. The success rate of modeling was associated with accuracy and separation of bile duct ligation position, intensity, presence of bile duct branches and animal-related individual differences.
2 Acute liver cell injury after bile duct obstruction gradually worsened, the third day after biliary obstruction, is the strongest point in time in acute liver cell damage response, then the organism entered the self-regulation and the repair process.7 days after biliary obstruction, activation with differentiation of reserve cells, the repair process of liver cells accompanied by fibrous tissue proliferation, fibrosis occurs, but not found in typical false liver lobule formation.
3 It was found that oval cells involved in liver cell injury in acute biliary obstruction in the repair process.Hepatic oval cells in liver tissue is not only on the most sensitive sexual impairment of a cell, is also involved in the leading cells of liver damage repair. The oval cell proliferation and collagen fiber proliferation was similar in damaged liver.
引文
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[38]Weiss MC,St rick H,March D,et al.Isolation and characterization of mouse hepatic stem cells in vitro[J].Semi Liver Dis,2003;23:313-324.
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[42]Grompe M.The role of bone marrow stem cells in liver regeneration[J]. Semin Liver Dis 2003;23:363-372
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