膽管梗阻大鼠模型中卵原細(xì)胞的超微病理結(jié)構(gòu)和時序性變化的研究
發(fā)布時間：2018-08-04 10:20
【摘要】：一、背景和目的 在肝膽外科臨床中,膽管梗阻、膽汁淤積是常見的病理環(huán)境,較長時間梗阻,可誘發(fā)永久性肝損害,甚至發(fā)展成肝纖維化及肝硬化,是臨床治療的難題,相關(guān)發(fā)病機(jī)制基礎(chǔ)研究有現(xiàn)實(shí)意義。 現(xiàn)已發(fā)現(xiàn)人類慢性肝病組織如肝硬化、亞急性肝壞死后肝再生、兒童先天性肝外膽管閉鎖、遺傳性血色病、慢性病毒性肝炎、原發(fā)性肝癌中都存在類似于卵圓細(xì)胞的肝前體細(xì)胞。這種肝前體細(xì)胞定位于匯管區(qū)、纖維間隔、匯管區(qū)旁肝實(shí)質(zhì)、假小葉及炎癥邊界。隨著肝臟卵圓細(xì)胞特異性標(biāo)記物的發(fā)現(xiàn),卵圓細(xì)胞相關(guān)研究成為熱點(diǎn),特別是肝臟卵圓細(xì)胞參與肝臟損傷修復(fù)、肝臟纖維化的相關(guān)研究。這些為研究肝臟損傷的保護(hù)、治療及肝纖維化的形成機(jī)制提供了最新途徑。 因此,本研究通過結(jié)扎Wistar大鼠膽總管,模擬膽管梗阻病理狀態(tài),通過免疫組化、PCR、透射電鏡技術(shù),探討這一病理過程肝臟卵圓細(xì)胞在膽管梗阻肝臟纖維化過程中的變化與發(fā)揮的作用。 二、材料與方法 雄性Wistar大鼠60只,體重250-300克,健康,無明顯畸形,將動物隨機(jī)分成兩組,一組(30只)作為實(shí)驗組實(shí)施近肝門端膽總管單線結(jié)扎(BDL術(shù))；另一組(30只)作為對照組實(shí)施假手術(shù),開腹游離膽總管但不結(jié)扎。術(shù)后相同條件下飼養(yǎng)。分別于術(shù)后第1天、2天、3天、7天、14天、21天處死大鼠,每組各處死5只,取肝右葉應(yīng)用4%多聚甲醛固定,留作免疫組化；取肝左葉-80℃凍存,留作RT-PCR檢測；肝中葉小片肝組織,固定后留作電鏡觀察。 1、通過肉眼及HE染色觀察膽管梗阻不同時間點(diǎn)肝臟形態(tài)改變。 2、通過免疫組化,OV-6標(biāo)記卵圓細(xì)胞,觀察不同時間點(diǎn)卵圓細(xì)胞的數(shù)目、分布。 3、通過投射電子顯微鏡觀察卵原細(xì)胞的超微結(jié)構(gòu)變化。 4、通過PCR檢測各目的基因：肝細(xì)胞生長因子(HGF),膠原蛋白I (COL I),觀察不同時間點(diǎn)各基因的表達(dá)情況。 三、結(jié)果 1、大體結(jié)果 Wistar大鼠膽管梗阻后可見肝臟黃染并腫脹,肝臟淤血、水腫。福爾馬林固定后部分大鼠的肝葉標(biāo)本,可見表面粗糙,顏色灰白等肝組織早期肝纖維化的表現(xiàn)。對照組：肝臟標(biāo)本各肝葉色澤紅潤,表面光滑。 2、HE染色結(jié)果： 對照組：肝組織結(jié)構(gòu)正常。實(shí)驗組：術(shù)后第1天見少量嗜中性粒細(xì)胞和淋巴細(xì)胞浸潤；術(shù)后第2天少許新增生無管腔的小膽管,少量嗜中性粒細(xì)胞和淋巴細(xì)胞浸潤；術(shù)后第3天新增生的細(xì)小膽管和無管腔的小膽管,嗜中性粒細(xì)胞和淋巴細(xì)胞浸潤較術(shù)后第2天明顯增加,肝細(xì)胞輕度變性,可見灶狀和片狀壞死,肝組織匯管區(qū)可見膽管增生和纖維組織細(xì)胞增生,偶見膽管擴(kuò)張；術(shù)后第7天肝細(xì)胞出現(xiàn)變性壞死發(fā)生率增加及程度加重,重者見片狀出血和壞死,肝組織門區(qū)可見膽管增生和纖維細(xì)胞增生；術(shù)后14天小葉結(jié)構(gòu)受到破壞,可見肝細(xì)胞空泡變性及壞死；術(shù)后21天小葉結(jié)構(gòu)破壞更加嚴(yán)重,大量肝細(xì)胞壞死。隨時間進(jìn)展肝臟損傷、纖維化程度逐漸加重。 3、免疫組化結(jié)果 OV-6免疫組化陽性染色的細(xì)胞數(shù)目及分布范圍隨著梗阻時間的延長而增加,實(shí)驗組和對照組有明顯差異。OV-6陽性細(xì)胞表達(dá)部位主要位于匯管區(qū)膽管及肝間質(zhì)新增生膽管及無管腔的小膽管細(xì)胞胞漿中。 4、電子顯微鏡觀察結(jié)果 對照組：肝組織及肝細(xì)胞結(jié)構(gòu)基本正常。實(shí)驗組：術(shù)后1天血管旁可見少量卵圓形核細(xì)胞,有少量圓鈍的胞質(zhì)突起,核漿比大,胞質(zhì)量少,細(xì)胞器數(shù)量少；術(shù)后2天肝細(xì)胞間也可找到一些卵圓形細(xì)胞,細(xì)胞切面呈鐘形或胖橄欖形,核近似卵圓形,核大,核漿比大,胞質(zhì)少,發(fā)育差；術(shù)后3天部分肝血竇內(nèi)皮損傷,內(nèi)皮細(xì)胞斷裂崩解,內(nèi)皮細(xì)胞核小,異染色質(zhì)呈濃染的團(tuán)塊,邊集于核膜下�？莘窦�(xì)胞內(nèi)吞噬泡數(shù)量較多,細(xì)胞間隙內(nèi)卵圓形核細(xì)胞多見；術(shù)后7天肝細(xì)胞板出現(xiàn)大的空隙,或僅殘存細(xì)胞框架,一些肝細(xì)胞呈不可逆損傷,一些細(xì)胞呈凋亡樣壞死,肝細(xì)胞間可見多形核白細(xì)胞存在,一些細(xì)胞僅可分辨核的大小差異,細(xì)胞無可分辨的細(xì)胞細(xì)節(jié),在形態(tài)尚好的部位,仍可找到少量存活的卵圓核細(xì)胞,已向肝細(xì)胞方向分化；術(shù)后14天肝細(xì)胞間可見一些立方形細(xì)胞,4-5個細(xì)胞形成片塊,細(xì)胞間可見小管樣結(jié)構(gòu),兩端的細(xì)胞間有緊密連接,小管內(nèi)有微絨毛伸入,腔內(nèi)無內(nèi)容物,核形近似卵圓,但不甚規(guī)則,核膜有凹陷,細(xì)胞器中等發(fā)育,細(xì)胞片塊與肝細(xì)胞有連接；術(shù)后21天一些膠原纖維束提示竇周間隙的位置。肝細(xì)胞間可見卵圓形核細(xì)胞片塊,其中有的細(xì)胞含大量脂滴；有的細(xì)胞是成纖維細(xì)胞,細(xì)胞周圍有大量膠原纖維存在；其余細(xì)胞性質(zhì)不可辨。 5、RT-PCR結(jié)果 在對照組和實(shí)驗組大鼠肝臟中均能檢測出目的基因的表達(dá)。統(tǒng)計分析顯示兩組COLⅠ的表達(dá)差異從第1天開始有統(tǒng)計學(xué)意義,HGF的表達(dá)差異從第3天開始有統(tǒng)計學(xué)意義。對實(shí)驗組不同天數(shù)組間的表達(dá)研究發(fā)現(xiàn)COLⅠ在3-7天無統(tǒng)計學(xué)意義,HGF在1-3天、7-21天無統(tǒng)計學(xué)意義,而其他相鄰各組間均有統(tǒng)計學(xué)意義,COLⅠ指標(biāo)1-3天增長趨勢最明顯,HGF指標(biāo)3-7天增長趨勢最明顯。 四、結(jié)論 1、研究發(fā)現(xiàn)肝外膽管結(jié)扎造成膽管梗阻的大鼠模型,其肝臟呈現(xiàn)膽汁淤積性、進(jìn)行性加重的肝臟受損表現(xiàn)。卵圓細(xì)胞參與膽管梗阻后損傷的修復(fù)過程,其時序性變化趨勢與肝臟修復(fù)相關(guān)細(xì)胞因子變化趨勢相似,可能參與肝臟受損后的修復(fù)過程。 2、利用電子顯微鏡觀察到卵原細(xì)胞的超微結(jié)構(gòu)形態(tài),描述了其細(xì)胞特點(diǎn)及周圍結(jié)構(gòu)的形態(tài)特點(diǎn),證實(shí)了卵原細(xì)胞的存在,直觀的觀察到其時序性過程中的變化。 3、研究發(fā)現(xiàn)實(shí)驗組肝臟纖維化相關(guān)基因表達(dá)明顯高于對照組,并且隨著梗阻天數(shù)的增加表達(dá)量增加,其中COLⅠ可顯示纖維化的進(jìn)程,HGF與肝臟受損后的修復(fù)過程有關(guān)。 4、研究發(fā)現(xiàn)在肝纖維化過程中的3-7天是肝臟受損過程的特殊時期,第3天之前以肝臟受損過程為主要表現(xiàn)；第3天開始出現(xiàn)修復(fù)損傷表現(xiàn),纖維化趨勢減弱；第7天之后為持續(xù)的的肝臟損傷、纖維化進(jìn)程。
[Abstract]:First, the background and the purpose
In the Department of hepatobiliary surgery, bile duct obstruction and cholestasis are common pathological conditions. Long time obstruction can induce permanent liver damage, and even develop into liver fibrosis and cirrhosis. It is a difficult problem in clinical treatment. The basic research of related pathogenesis is of practical significance.
It has been found that human chronic liver diseases such as liver cirrhosis, subacute hepatic necrosis after subacute hepatic necrosis, congenital extrahepatic bile duct atresia in children, hereditary hemochromatosis, chronic viral hepatitis, and primary liver cancer are all similar to oval cells in the hepatic precursor cells. False lobules and inflammatory boundaries. With the discovery of specific markers for oval cells in the liver, oval cells related research become hot spots, especially liver oval cells participate in the repair of liver injury and liver fibrosis, which provide the latest approach to study the protection of liver injury, treatment and the formation mechanism of liver fibrosis.
Therefore, by ligating Wistar rat common bile duct and simulating the pathological state of bile duct obstruction, the changes and roles of hepatic oval cells in the process of hepatic fibrosis in the bile duct obstruction were discussed by immunohistochemistry, PCR and transmission electron microscopy.
Two, materials and methods
60 male Wistar rats, weighing 250-300 grams, healthy and no obvious malformation, were randomly divided into two groups. One group (30) was used as the experimental group to carry out the unilateral ligation of the common bile duct of the liver (BDL); the other group (30) was used as a control group to carry out the sham operation, open the free common bile duct and no ligation after the operation. First The rats were killed in days, 2 days, 3 days, 7 days, 14 days and 21 days, and 5 rats were killed in each group. The right lobe of the liver was fixed with 4% polyformaldehyde and retained for immunohistochemical staining. The left lobe of the liver was stored at -80 for RT-PCR, and the liver tissue of the middle lobe of the liver was kept for electron microscopy after fixation.
1, the morphological changes of bile duct obstruction at different time points were observed by naked eye and HE staining.
2, by immunohistochemical staining, OV-6 labeled oval cells to observe the number and distribution of oval cells at different time points.
3, the ultrastructural changes of oocytes were observed by projection electron microscopy.
4. Hepatocyte growth factor (HGF) and collagen I (COL I) were detected by PCR, and the expression of each gene was observed at different time points.
Three, the result
1, gross results
Wistar rat bile duct obstruction can be seen after the liver yellow staining and swelling, liver congestion, edema. After formalin fixed part of the rat liver specimens, visible surface roughness, color gray and other liver tissue early liver fibrosis performance. Control group: liver specimens of the liver color red, surface smooth.
2, HE staining results:
In the control group, the liver tissue structure was normal. In the experimental group, a small amount of neutrophils and lymphocyte infiltration were seen on the first day after the operation, and a few small bile ducts with neutrophils and neutrophils and lymphocytes infiltrated on the second day after the operation, and the neutrophils and lymphatic cells and lymph nodes of newly proliferated small bile ducts and cavities, neutrophils and lymphatic lymph nodes on third days after the operation. The cell infiltration was significantly increased on the second day after the operation, the liver cells were slightly denatured, and the focal and flaky necrosis were seen. The bile duct hyperplasia and fibrous cell proliferation were seen in the liver tissue, and the bile duct dilatation was seen occasionally. The incidence of degeneration and necrosis was increased and the degree was aggravated on the seventh day after the operation, and the severe hemorrhage and necrosis were seen in the severe cases, and the portal area of the liver was visible. Bile duct hyperplasia and fibroblast proliferation; the structure of the lobule was damaged on the 14 day after the operation, and the vacuoles and necrosis of the liver cells were seen. The destruction of the structure of the lobule was more serious on the 21 day after the operation, and a large number of liver cells were necrotic.
3, immunohistochemical results
The number and distribution of OV-6 immunohistochemical positive staining cells increased with the prolongation of the obstruction time. There was a significant difference between the experimental group and the control group. The expression of.OV-6 positive cells was mainly located in the bile duct and the new cholangioplastic bile duct and the small bile duct cell cytoplasm without the lumen.
4, the observation result of electron microscope
In the control group, the liver tissue and the liver cell structure were basically normal. In the experimental group, a small number of oval nuclear cells were visible near the vessel 1 days after the operation, with a small number of blunt cytosolic protuberances, large nuclear pulp ratio, less cell mass and less organelles, and some oval cells could be found between the hepatocytes on the 2 day after the operation. The cells were bell shaped or fat olive shaped, and the nucleus approximated the egg. Round, large nuclear, large nuclear pulp ratio, less cytoplasm, poor development, 3 days after the operation, partial hepatic sinusoidal endothelial injury, endothelial cell rupture disintegration, small endothelial cell nucleus, heterochromatin under the dense mass, the edge of the nuclear membrane. The number of phagocytic vesicles in the Kupffer cell is more, and the oval cells in the cell space are more common; the liver cell board appears large empty after 7 days after the operation. Gap, or only residual cell frame, some liver cells are irreversible damage, some cells are apoptotic like necrosis, hepatic cells can be found to exist polymorphonuclear leukocytes, some cells can only distinguish the size difference between the nuclei, the cells have no discernible cell details, and a small number of surviving oval nuclear cells can still be found in the good shape of the cells, and the cells have been found to the liver cells. 14 days after the operation, there were cubic cells, 4-5 cells forming pieces, small tube like structures between the cells, close connections between the cells at both ends, microvilli in the canaliculus, no contents in the canaliculus, and nuclear shape similar to oval, but not very regular, the nuclear membrane was depressed, the organelles were moderately developed, cell block and liver thin. In the 21 day after the operation, some collagen fiber bundles suggest the location of the peri sinus space. The cells of the oval nucleus cells can be seen between the hepatocytes, some of them contain a large amount of lipid droplets, some cells are fibroblasts, and a large number of collagen fibers exist around the cells; the other cells are not distinguishes.
5, RT-PCR results
The expression of the target gene was detected in the liver of the control group and the experimental group. The statistical analysis showed that the difference in expression of the two groups of COL I was statistically significant from first days, and the difference in expression of HGF was statistically significant from third days. The expression of COL I between the different days of the experimental group found no statistical significance in the 3-7 days, HGF On the 1-3 day, the 7-21 days were not statistically significant, but the other adjacent groups were statistically significant. The growth trend of COL I index in 1-3 days was the most obvious, and the growth trend of the 3-7 days was the most obvious.
Four. Conclusion
1, the rat model of bile duct obstruction caused by extrahepatic bile duct ligation was found. The liver showed cholestasis and progressively aggravated liver damage. The repair process of oval cells involved in the injury after bile duct obstruction was similar to that of the liver repair related cytokines. It may be involved in the repair of liver damage. Complex process.
2, the ultrastructure of oocyte was observed by electron microscope, the characteristics of the cells and the morphological characteristics of the surrounding structure were described, and the existence of oocyte was confirmed, and the changes in the time sequence of the oocyte were observed.
3, the study found that the expression of liver fibrosis related genes in the experimental group was significantly higher than that in the control group, and the expression increased with the increase of the number of obstructive days, and COL I showed the process of fibrosis, and HGF was related to the repair process after liver damage.
4, the study found that the 3-7 day in the process of liver fibrosis was a special period of liver damage, and the liver damage was the main manifestation before third days, and the repair injury appeared at the beginning of the third day and the trend of fibrosis weakened; after seventh days, the liver injury and fibrotic process were continued.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R575
本文編號：2163615
[Abstract]:First, the background and the purpose
In the Department of hepatobiliary surgery, bile duct obstruction and cholestasis are common pathological conditions. Long time obstruction can induce permanent liver damage, and even develop into liver fibrosis and cirrhosis. It is a difficult problem in clinical treatment. The basic research of related pathogenesis is of practical significance.
It has been found that human chronic liver diseases such as liver cirrhosis, subacute hepatic necrosis after subacute hepatic necrosis, congenital extrahepatic bile duct atresia in children, hereditary hemochromatosis, chronic viral hepatitis, and primary liver cancer are all similar to oval cells in the hepatic precursor cells. False lobules and inflammatory boundaries. With the discovery of specific markers for oval cells in the liver, oval cells related research become hot spots, especially liver oval cells participate in the repair of liver injury and liver fibrosis, which provide the latest approach to study the protection of liver injury, treatment and the formation mechanism of liver fibrosis.
Therefore, by ligating Wistar rat common bile duct and simulating the pathological state of bile duct obstruction, the changes and roles of hepatic oval cells in the process of hepatic fibrosis in the bile duct obstruction were discussed by immunohistochemistry, PCR and transmission electron microscopy.
Two, materials and methods
60 male Wistar rats, weighing 250-300 grams, healthy and no obvious malformation, were randomly divided into two groups. One group (30) was used as the experimental group to carry out the unilateral ligation of the common bile duct of the liver (BDL); the other group (30) was used as a control group to carry out the sham operation, open the free common bile duct and no ligation after the operation. First The rats were killed in days, 2 days, 3 days, 7 days, 14 days and 21 days, and 5 rats were killed in each group. The right lobe of the liver was fixed with 4% polyformaldehyde and retained for immunohistochemical staining. The left lobe of the liver was stored at -80 for RT-PCR, and the liver tissue of the middle lobe of the liver was kept for electron microscopy after fixation.
1, the morphological changes of bile duct obstruction at different time points were observed by naked eye and HE staining.
2, by immunohistochemical staining, OV-6 labeled oval cells to observe the number and distribution of oval cells at different time points.
3, the ultrastructural changes of oocytes were observed by projection electron microscopy.
4. Hepatocyte growth factor (HGF) and collagen I (COL I) were detected by PCR, and the expression of each gene was observed at different time points.
Three, the result
1, gross results
Wistar rat bile duct obstruction can be seen after the liver yellow staining and swelling, liver congestion, edema. After formalin fixed part of the rat liver specimens, visible surface roughness, color gray and other liver tissue early liver fibrosis performance. Control group: liver specimens of the liver color red, surface smooth.
2, HE staining results:
In the control group, the liver tissue structure was normal. In the experimental group, a small amount of neutrophils and lymphocyte infiltration were seen on the first day after the operation, and a few small bile ducts with neutrophils and neutrophils and lymphocytes infiltrated on the second day after the operation, and the neutrophils and lymphatic cells and lymph nodes of newly proliferated small bile ducts and cavities, neutrophils and lymphatic lymph nodes on third days after the operation. The cell infiltration was significantly increased on the second day after the operation, the liver cells were slightly denatured, and the focal and flaky necrosis were seen. The bile duct hyperplasia and fibrous cell proliferation were seen in the liver tissue, and the bile duct dilatation was seen occasionally. The incidence of degeneration and necrosis was increased and the degree was aggravated on the seventh day after the operation, and the severe hemorrhage and necrosis were seen in the severe cases, and the portal area of the liver was visible. Bile duct hyperplasia and fibroblast proliferation; the structure of the lobule was damaged on the 14 day after the operation, and the vacuoles and necrosis of the liver cells were seen. The destruction of the structure of the lobule was more serious on the 21 day after the operation, and a large number of liver cells were necrotic.
3, immunohistochemical results
The number and distribution of OV-6 immunohistochemical positive staining cells increased with the prolongation of the obstruction time. There was a significant difference between the experimental group and the control group. The expression of.OV-6 positive cells was mainly located in the bile duct and the new cholangioplastic bile duct and the small bile duct cell cytoplasm without the lumen.
4, the observation result of electron microscope
In the control group, the liver tissue and the liver cell structure were basically normal. In the experimental group, a small number of oval nuclear cells were visible near the vessel 1 days after the operation, with a small number of blunt cytosolic protuberances, large nuclear pulp ratio, less cell mass and less organelles, and some oval cells could be found between the hepatocytes on the 2 day after the operation. The cells were bell shaped or fat olive shaped, and the nucleus approximated the egg. Round, large nuclear, large nuclear pulp ratio, less cytoplasm, poor development, 3 days after the operation, partial hepatic sinusoidal endothelial injury, endothelial cell rupture disintegration, small endothelial cell nucleus, heterochromatin under the dense mass, the edge of the nuclear membrane. The number of phagocytic vesicles in the Kupffer cell is more, and the oval cells in the cell space are more common; the liver cell board appears large empty after 7 days after the operation. Gap, or only residual cell frame, some liver cells are irreversible damage, some cells are apoptotic like necrosis, hepatic cells can be found to exist polymorphonuclear leukocytes, some cells can only distinguish the size difference between the nuclei, the cells have no discernible cell details, and a small number of surviving oval nuclear cells can still be found in the good shape of the cells, and the cells have been found to the liver cells. 14 days after the operation, there were cubic cells, 4-5 cells forming pieces, small tube like structures between the cells, close connections between the cells at both ends, microvilli in the canaliculus, no contents in the canaliculus, and nuclear shape similar to oval, but not very regular, the nuclear membrane was depressed, the organelles were moderately developed, cell block and liver thin. In the 21 day after the operation, some collagen fiber bundles suggest the location of the peri sinus space. The cells of the oval nucleus cells can be seen between the hepatocytes, some of them contain a large amount of lipid droplets, some cells are fibroblasts, and a large number of collagen fibers exist around the cells; the other cells are not distinguishes.
5, RT-PCR results
The expression of the target gene was detected in the liver of the control group and the experimental group. The statistical analysis showed that the difference in expression of the two groups of COL I was statistically significant from first days, and the difference in expression of HGF was statistically significant from third days. The expression of COL I between the different days of the experimental group found no statistical significance in the 3-7 days, HGF On the 1-3 day, the 7-21 days were not statistically significant, but the other adjacent groups were statistically significant. The growth trend of COL I index in 1-3 days was the most obvious, and the growth trend of the 3-7 days was the most obvious.
Four. Conclusion
1, the rat model of bile duct obstruction caused by extrahepatic bile duct ligation was found. The liver showed cholestasis and progressively aggravated liver damage. The repair process of oval cells involved in the injury after bile duct obstruction was similar to that of the liver repair related cytokines. It may be involved in the repair of liver damage. Complex process.
2, the ultrastructure of oocyte was observed by electron microscope, the characteristics of the cells and the morphological characteristics of the surrounding structure were described, and the existence of oocyte was confirmed, and the changes in the time sequence of the oocyte were observed.
3, the study found that the expression of liver fibrosis related genes in the experimental group was significantly higher than that in the control group, and the expression increased with the increase of the number of obstructive days, and COL I showed the process of fibrosis, and HGF was related to the repair process after liver damage.
4, the study found that the 3-7 day in the process of liver fibrosis was a special period of liver damage, and the liver damage was the main manifestation before third days, and the repair injury appeared at the beginning of the third day and the trend of fibrosis weakened; after seventh days, the liver injury and fibrotic process were continued.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R575
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