Rho GTPase对血吸虫病肝纤维化鼠肝窦毛细血管化的调控作用及其机制研究
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摘要
第一部分血吸虫病肝纤维化的肝窦病变实验研究
目的研究日本血吸虫感染致肝纤维化鼠的肝窦病变。
方法对40只日本血吸虫感染致肝纤维化鼠和10只正常鼠取肝组织行光镜和电镜观察肝窦病变;免疫组织化学技术检测CD31、FVIIIR-Ag。
结果HE染色示汇管区可见虫卵沉积,虫卵周围炎性细胞浸润。Masson三色染色见大部分肝血窦周围Disse腔有纤细的蓝绿色胶原纤维沉积。透射电镜下见肝窦内皮受损严重,窗孔明显减少,胞饮泡减少甚至消失,细胞外侧有基底膜形成,肝细胞肝窦面的微绒毛减少或断裂。免疫组化示肝窦内皮细胞膜表达CD31、FVIIIR-Ag阳性或强阳性;正常对照组呈阴性或低水平表达。
结论血吸虫病肝纤维化时普遍存在肝窦毛细血管化,其中肝窦内皮细胞转分化可能与其形成密切相关。
第二部分CTGF在血吸虫病肝纤维化鼠肝窦内皮细胞表达及意义
目的通过动态观察结缔组织生长因子(connective tissue growth factor, CTGF)在血吸虫病性肝纤维化鼠肝窦内皮细胞表达水平的时相变化,探讨CTGF、肝窦内皮细胞与肝窦内皮下基底膜形成的关系。
方法采用腹部敷贴法感染血吸虫尾蚴建立血吸虫病性肝纤维化模型,模型组和正常对照组均为40只。于45d、60d、90d、120d取肝组织标本,HE、Masson染色和透射电镜观察模型病理变化;免疫组织化学技术检测CTGF、ColIV和LN在小鼠肝脏组织中的定位、发布,并应用彩色图像分析仪进行半定量分析;Western blotting检测CTGF蛋白;RT–PCR检测CTGFmRNA的表达。
结果血吸虫病肝纤维化鼠肝窦内皮细胞表达CTGF蛋白阳性或强阳性,肝窦壁LN、ColIV表达水平增高,且随着肝纤维化的发展,CTGF和LN、ColIV表达逐渐增强,同步可见肝窦内皮下基底膜逐渐增厚;正常对照组呈阴性或低水平表达。图像定量分析两组平均吸光度值、平均灰度值和阳性面积比具有统计学意义(P < 0. 05)。相关分析CTGF蛋白与LN、ColIV水平呈正相关(r=0.7512、0.6417 P <0.01)。
结论血吸虫病肝纤维化时小鼠肝窦内皮细胞调控细胞外基质产生,通过CTGF蛋白表达上调,导致ColIV、LN分泌增加,参与肝窦内皮下基底膜形成,从而引起肝内微循环障碍。
第三部分Rho GTPase对血吸虫病鼠肝窦毛细血管化的调控作用
目的探讨Rho GTPase在肝窦内皮细胞转分化过程中的调控作用,及其对血吸虫病性鼠肝窦毛细血管化病变的影响和可能机制。
方法采用腹部敷贴法感染血吸虫尾蚴建立血吸虫病性肝纤维化模型,于13WBiltricide顿服杀虫,14W追加hydroxyfasudil。13W时正常对照组(A组,10只)与血吸虫病组(B组,6只),16W、19W和21W后(B组、杀虫实验对照组(C组)、血吸虫病+hydroxyfasudil组(D组)、杀虫+hydroxyfasudil组(E组)各6只)剖腹取肝组织。分别作HE、Masson染色和透射电镜观察;免疫组化检测p-moesin、CTGF、CD31、ColIV和LN;Western blotting检测p-moesin、CTGF、Rho A、ColIV和LN蛋白表达;RT–PCR检测CTGF、Rho A、ROCKII mRNA水平。
结果与A组相比,动态观察B组肝组织Rho A、ROCKII及CTGF mRNA表达水平明显上升,p-moesin、CTGF、Rho A、ColIV和LN蛋白表达量也增高。给予干预措施后,与C组及其它组相比,E组CTGF mRNA表达于16W显著下调,同时显示CTGF、LN、ColIV蛋白水平也降低。与B组相比,D组、E组p-moesin蛋白降低,16W时最为显著,但D组于19W开始p-moesin表达量渐恢复到原水平,其中E组明显低于D组。肝窦的超微结构观察,于21W时C组分别与B、D组相比,浸润的炎性细胞明显减少,Disse腔内胶原纤维有所减少,但肝窦内皮细胞窗孔、肝窦内皮下基底膜无明显差异。E组与C组比较肝细胞器形态明显恢复,可见窗孔,未见基底膜。
结论Rho GTPase在调控血吸虫病性鼠肝窦内皮细胞转分化过程中,通过上调CTGF和p-moesin发挥作用,抑制Rho GTPase信号通路有可能为防治肝窦毛细血管化提供新的有效靶点。
PART I Hepatic Sinusoidal Pathology of Hepatic Fibrosis Mouses Induced by Infection of Schistosoma Japonicum.
Objective To investigate the hepatic sinusoidal pathology of hepatic fobrosis mouses in duced by infection of Schistosoma japonicum .
Methods Liver tissues from 30 hepatic cirrhotic mouses infected by Schistosoma japonicum and 10 normal mouses were removed and observed under light and electronmicroscopy for hepatic sinusoidal pathology. distribution of CD31、FVIIIRAg were detected by imunohistochemistry,.
Results Hematoxylin and Eosin (HE) staining indicated schistosome egg aggradation in the hilum and inflammatory cell infilt ration around the schistosome eggs. Masson trichrome staining showed hyperplasia of blue-green fiber connective tissue around Disse spaces mostly. Under transmission electronmicroscopy , it was found there was serious damage of hepatic sinusoidal endothelium cells , collapse of most cells , infilt ration of inflammatory cells in hepatic sinusoidal , expansion of small bile duct , decreased or injured microfloss , and capillarization of hepatic sinusoidal. Compared with control group, CD31、FVIIIRAg protein staining of sinusoidal endothelial cell in schistosomal hepatic fibrosis mouses increased significantly .
Conclusion Our results suggest that a transition of liver sinusoidal endothelial cells may be involved with the development of sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
PART II Expression of connective tissue growth factor in sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses.
Objective to explore the possible correlations with CTGF、liver sinusoidal endothelial cell and the formation of basal membrane under hepatic sinusoidal endothelial cell by observing the expression of connective tissue growth factor(CTGF)in sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses.
Methods the liver fibrosis model was established by abdominal infected with schistosomal cercaria in 40 mouse,and the contral group 40 yet.the dynamic changes of liver fibrosis was observed at different time points(45d、60d、90d、120d)by optic and electonmicrocopy.the distribution of CTGF、collagen type IV(ColIV)and laminin(LN)were detected by imunohistochemistry,and adopt quantitive analysis;proteins of CTGF were detected by Western blotting;CTGFmRNAs were detected by RT–PCR.
Results Compared with control group, CTGF protein staining of sinusoidal endothelial cell in schistosomal hepatic fibrosis mouses increased significantly at 120d and companied by the increases of LN、ColIV protein in hepatic sinusoidal walls(P < 0. 05)and the expression of CTGFmRNA was significant increased, and the expression of CTGF protein was significant corrected to the level of LN、ColIV(r=0.7512、0.6417 P <0. 01)yet.
Conclusin hepatic sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses regulate producing of extracellular matrix by upregulated expression of CTGF which induced the increases of LN、ColIV levels,and involve the formation of basal membrane under hepatic sinusoidal endothelial cell.
PART III Effects of a transition of liver sinusoidal endothelial cells regulated by Rho GTPase signaling on sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
Objective To investigate Rho GTPase mediated regulation of a transition of liver sinusoidal endothelial cells on sinusoidal capillarization with schistosomal hepatic fibrosis mouses and possible mechanism.
Methods The liver fibrosis model was established by abdominal infected with schistosomal cercaria in 88 mouse,treated with Biltricide in 13W and hydroxyfasudil in 14W.And then they were divided into the following 5 groups,i.e. A,contral groups. B,model groups. C,treated with Biltricide groups.D,treated with hydroxyfasudil groups.E,treated with Biltricide+hydroxyfasudil groups.In 13W(A group 10 mouses and B group 6 mouses),in 16W、19W and 21W(B、D、C、E group,each group 6 mouses),the mouses were sacrificed,respectively.The relative area of liver fibrosis on pathological section was semi-quantitatively determined and assessed by HE、Masson stain、electonmicrocopy and imunohistochemistry.And p-moesin、CTGF、Rho A、ColIV and LN protein expressions were assessed by Western blotting,CTGF、Rho A、ROCKII mRNA expressions were assessed by RT–PCR.
Results Compared with A group,the mRNA level of Rho A、ROCKII and CTGF were significantly increased(P<0.05)and the protein expression of p-moesin、CTGF、RhoA、ColIV and LN were increased(P<0.05)in B group.After intervension with Biltricide and/or hydroxyfasudil,CTGF mRNA expression significantly decreased(P<0.05)in E group in 16W and the protein expression of CTGF、ColIV and LN were decreased(P<0.05)compared with other groups,and the expression of p-moesin in E group were markedly lower than that of D group(P<0.05).Electonmicrocopy show liver sinusoidal of the mouses in E group was significantly recovered compared with other groups.And there was no difference between B group and D group.
Conclusin Our results suggest that an upregulation of Rho GTPase that contributes to increased CTGF expressions and phosphorylation of moesin may induce a transition of liver sinusoidal endothelial cells on sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
目的研究日本血吸虫感染致肝纤维化鼠的肝窦病变。
方法对40只日本血吸虫感染致肝纤维化鼠和10只正常鼠取肝组织行光镜和电镜观察肝窦病变;免疫组织化学技术检测CD31、FVIIIR-Ag。
结果HE染色示汇管区可见虫卵沉积,虫卵周围炎性细胞浸润。Masson三色染色见大部分肝血窦周围Disse腔有纤细的蓝绿色胶原纤维沉积。透射电镜下见肝窦内皮受损严重,窗孔明显减少,胞饮泡减少甚至消失,细胞外侧有基底膜形成,肝细胞肝窦面的微绒毛减少或断裂。免疫组化示肝窦内皮细胞膜表达CD31、FVIIIR-Ag阳性或强阳性;正常对照组呈阴性或低水平表达。
结论血吸虫病肝纤维化时普遍存在肝窦毛细血管化,其中肝窦内皮细胞转分化可能与其形成密切相关。
第二部分CTGF在血吸虫病肝纤维化鼠肝窦内皮细胞表达及意义
目的通过动态观察结缔组织生长因子(connective tissue growth factor, CTGF)在血吸虫病性肝纤维化鼠肝窦内皮细胞表达水平的时相变化,探讨CTGF、肝窦内皮细胞与肝窦内皮下基底膜形成的关系。
方法采用腹部敷贴法感染血吸虫尾蚴建立血吸虫病性肝纤维化模型,模型组和正常对照组均为40只。于45d、60d、90d、120d取肝组织标本,HE、Masson染色和透射电镜观察模型病理变化;免疫组织化学技术检测CTGF、ColIV和LN在小鼠肝脏组织中的定位、发布,并应用彩色图像分析仪进行半定量分析;Western blotting检测CTGF蛋白;RT–PCR检测CTGFmRNA的表达。
结果血吸虫病肝纤维化鼠肝窦内皮细胞表达CTGF蛋白阳性或强阳性,肝窦壁LN、ColIV表达水平增高,且随着肝纤维化的发展,CTGF和LN、ColIV表达逐渐增强,同步可见肝窦内皮下基底膜逐渐增厚;正常对照组呈阴性或低水平表达。图像定量分析两组平均吸光度值、平均灰度值和阳性面积比具有统计学意义(P < 0. 05)。相关分析CTGF蛋白与LN、ColIV水平呈正相关(r=0.7512、0.6417 P <0.01)。
结论血吸虫病肝纤维化时小鼠肝窦内皮细胞调控细胞外基质产生,通过CTGF蛋白表达上调,导致ColIV、LN分泌增加,参与肝窦内皮下基底膜形成,从而引起肝内微循环障碍。
第三部分Rho GTPase对血吸虫病鼠肝窦毛细血管化的调控作用
目的探讨Rho GTPase在肝窦内皮细胞转分化过程中的调控作用,及其对血吸虫病性鼠肝窦毛细血管化病变的影响和可能机制。
方法采用腹部敷贴法感染血吸虫尾蚴建立血吸虫病性肝纤维化模型,于13WBiltricide顿服杀虫,14W追加hydroxyfasudil。13W时正常对照组(A组,10只)与血吸虫病组(B组,6只),16W、19W和21W后(B组、杀虫实验对照组(C组)、血吸虫病+hydroxyfasudil组(D组)、杀虫+hydroxyfasudil组(E组)各6只)剖腹取肝组织。分别作HE、Masson染色和透射电镜观察;免疫组化检测p-moesin、CTGF、CD31、ColIV和LN;Western blotting检测p-moesin、CTGF、Rho A、ColIV和LN蛋白表达;RT–PCR检测CTGF、Rho A、ROCKII mRNA水平。
结果与A组相比,动态观察B组肝组织Rho A、ROCKII及CTGF mRNA表达水平明显上升,p-moesin、CTGF、Rho A、ColIV和LN蛋白表达量也增高。给予干预措施后,与C组及其它组相比,E组CTGF mRNA表达于16W显著下调,同时显示CTGF、LN、ColIV蛋白水平也降低。与B组相比,D组、E组p-moesin蛋白降低,16W时最为显著,但D组于19W开始p-moesin表达量渐恢复到原水平,其中E组明显低于D组。肝窦的超微结构观察,于21W时C组分别与B、D组相比,浸润的炎性细胞明显减少,Disse腔内胶原纤维有所减少,但肝窦内皮细胞窗孔、肝窦内皮下基底膜无明显差异。E组与C组比较肝细胞器形态明显恢复,可见窗孔,未见基底膜。
结论Rho GTPase在调控血吸虫病性鼠肝窦内皮细胞转分化过程中,通过上调CTGF和p-moesin发挥作用,抑制Rho GTPase信号通路有可能为防治肝窦毛细血管化提供新的有效靶点。
PART I Hepatic Sinusoidal Pathology of Hepatic Fibrosis Mouses Induced by Infection of Schistosoma Japonicum.
Objective To investigate the hepatic sinusoidal pathology of hepatic fobrosis mouses in duced by infection of Schistosoma japonicum .
Methods Liver tissues from 30 hepatic cirrhotic mouses infected by Schistosoma japonicum and 10 normal mouses were removed and observed under light and electronmicroscopy for hepatic sinusoidal pathology. distribution of CD31、FVIIIRAg were detected by imunohistochemistry,.
Results Hematoxylin and Eosin (HE) staining indicated schistosome egg aggradation in the hilum and inflammatory cell infilt ration around the schistosome eggs. Masson trichrome staining showed hyperplasia of blue-green fiber connective tissue around Disse spaces mostly. Under transmission electronmicroscopy , it was found there was serious damage of hepatic sinusoidal endothelium cells , collapse of most cells , infilt ration of inflammatory cells in hepatic sinusoidal , expansion of small bile duct , decreased or injured microfloss , and capillarization of hepatic sinusoidal. Compared with control group, CD31、FVIIIRAg protein staining of sinusoidal endothelial cell in schistosomal hepatic fibrosis mouses increased significantly .
Conclusion Our results suggest that a transition of liver sinusoidal endothelial cells may be involved with the development of sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
PART II Expression of connective tissue growth factor in sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses.
Objective to explore the possible correlations with CTGF、liver sinusoidal endothelial cell and the formation of basal membrane under hepatic sinusoidal endothelial cell by observing the expression of connective tissue growth factor(CTGF)in sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses.
Methods the liver fibrosis model was established by abdominal infected with schistosomal cercaria in 40 mouse,and the contral group 40 yet.the dynamic changes of liver fibrosis was observed at different time points(45d、60d、90d、120d)by optic and electonmicrocopy.the distribution of CTGF、collagen type IV(ColIV)and laminin(LN)were detected by imunohistochemistry,and adopt quantitive analysis;proteins of CTGF were detected by Western blotting;CTGFmRNAs were detected by RT–PCR.
Results Compared with control group, CTGF protein staining of sinusoidal endothelial cell in schistosomal hepatic fibrosis mouses increased significantly at 120d and companied by the increases of LN、ColIV protein in hepatic sinusoidal walls(P < 0. 05)and the expression of CTGFmRNA was significant increased, and the expression of CTGF protein was significant corrected to the level of LN、ColIV(r=0.7512、0.6417 P <0. 01)yet.
Conclusin hepatic sinusoidal endothelial cell of schistosomal hepatic fibrosis mouses regulate producing of extracellular matrix by upregulated expression of CTGF which induced the increases of LN、ColIV levels,and involve the formation of basal membrane under hepatic sinusoidal endothelial cell.
PART III Effects of a transition of liver sinusoidal endothelial cells regulated by Rho GTPase signaling on sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
Objective To investigate Rho GTPase mediated regulation of a transition of liver sinusoidal endothelial cells on sinusoidal capillarization with schistosomal hepatic fibrosis mouses and possible mechanism.
Methods The liver fibrosis model was established by abdominal infected with schistosomal cercaria in 88 mouse,treated with Biltricide in 13W and hydroxyfasudil in 14W.And then they were divided into the following 5 groups,i.e. A,contral groups. B,model groups. C,treated with Biltricide groups.D,treated with hydroxyfasudil groups.E,treated with Biltricide+hydroxyfasudil groups.In 13W(A group 10 mouses and B group 6 mouses),in 16W、19W and 21W(B、D、C、E group,each group 6 mouses),the mouses were sacrificed,respectively.The relative area of liver fibrosis on pathological section was semi-quantitatively determined and assessed by HE、Masson stain、electonmicrocopy and imunohistochemistry.And p-moesin、CTGF、Rho A、ColIV and LN protein expressions were assessed by Western blotting,CTGF、Rho A、ROCKII mRNA expressions were assessed by RT–PCR.
Results Compared with A group,the mRNA level of Rho A、ROCKII and CTGF were significantly increased(P<0.05)and the protein expression of p-moesin、CTGF、RhoA、ColIV and LN were increased(P<0.05)in B group.After intervension with Biltricide and/or hydroxyfasudil,CTGF mRNA expression significantly decreased(P<0.05)in E group in 16W and the protein expression of CTGF、ColIV and LN were decreased(P<0.05)compared with other groups,and the expression of p-moesin in E group were markedly lower than that of D group(P<0.05).Electonmicrocopy show liver sinusoidal of the mouses in E group was significantly recovered compared with other groups.And there was no difference between B group and D group.
Conclusin Our results suggest that an upregulation of Rho GTPase that contributes to increased CTGF expressions and phosphorylation of moesin may induce a transition of liver sinusoidal endothelial cells on sinusoidal capillarization with schistosomal hepatic fibrosis mouses.
引文
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