肝窦内皮细胞损伤和表型改变在大鼠肝硬化门脉高压发生中的作用  

Role of injury and phenotype shift of liver sinusoidal endothelial cells in the development of portal hypertension of cirrhosis in rats

作　　者：王宪波[1] 刘平[1] 唐志鹏[1] 陆雄[1] 刘成海[1] 胡义扬[1] 徐列明[1] 顾宏图[1] 刘成[1] 

机构地区：[1]上海中医药大学肝病研究所,附属曙光医院肝硬化科上海201203

出　　处：《中国病理生理杂志》2005年第9期1811-1816,共6页Chinese Journal of Pathophysiology

基　　金：国家杰出青年科学基金资助项目(No.39825128);上海市重点学科项目资助

摘　　要：目的:探讨肝窦内皮细胞(SECs)损伤和表型改变与大鼠肝硬化门脉高压的关系。方法:采用二甲基亚硝胺(DMN)4周12次腹腔注射复制大鼠肝硬化模型,分别于造模后1d、2d、3d、1周、2周、4周、6周、8周作动态观察;肠系膜前静脉分支插管法测门脉压力(Ppv);透射电镜观察肝组织超微结构;免疫组化观察肝窦壁CD44和Ⅷ因子相关抗原(vWF)表达;Northernblot检测肝组织内皮素-1(ET-1)mRNA和内皮型一氧化氮合酶(eNOS)mRNA表达;Westernblot检测肝组织eNOS表达;放射免疫法测定血清透明质酸(HA)和肝组织ET-1含量。结果:DMN造模1d后CD44染色明显弱于正常对照组(P<0.05),SECs窗孔减少,血清HA含量显著高于正常对照组(P<0.05);DMN造模2d后vWF阳性染色明显强于正常对照组(P<0.05);DMN大鼠的Ppv与肝窦壁vWF表达量和血清HA含量呈显著正相关(P<0.05);造模2d和3d时ET-1mRNA表达强于正常对照组,ET-1含量轻度高于正常对照组;造模1d、2d和3d时eNOSmRNA表达强于正常对照组,而eNOS一直呈低水平状态。结论:SECs损伤和表型改变是DMN大鼠肝硬化门脉高压形成的病理基础之一;ET-1和NO产生的平衡失调,使肝内血流阻力增加,在门脉高压形成过程中起重要作用。AIM： To study the role of injury and phenotype shift of hver sinusoidal endothelial cells in the development of portal hypertension of liver cirrhosis in rats. METHODS： The rat hver cirrhosis model was estabhshed by peritoneal injection of dimethylnitrosamine （DMN） （at a dose of 10 mg·kg^-1, 3 times a week, for 4 weeks）. The dynamic changes of liver cirrhosis were observed at different time points （ 1 day, 2 days, 3 days, 1 week, 2 weeks, 4 weeks, 6 weeks and 8 weeks）. The pressure of por- tal vein （Ppv）, the expression of CD44, yon Willebrand factor （vWF）, endothelin- 1 （ET- 1） mRNA and endothehal nitric oxide synthase （eNOS） mRNA, the serum hyaluronic acid （HA） content and liver ET- 1 content were measured. RESULTS： Compared with the normal control rats, CD44 positive staining was weak in the 1 day model rats, and the numbers of fenestrae of sinusoidal endothelial cells （SECs） rapidly decreased, but serum HA content rapidly increased （ P 〈 0.05）. vWF positive staining in the 2 - day model rats was stronger than that in normal control rats （ P 〈 0.05）. There was a positive correlation between the Ppv and the vWF expression, serum HA content in the DMN - induced liver cirrhosis rats （ P 〈 0.05）. Compared with the normal control rots, ET- 1 mRNA expression increased in the 2 - day and 3 - day model rats, and ET- 1 content lightly increased, eNOS mRNA expression was stronger in the 1 - day, 2 - day and 3 - day model rats than that in normal control rots, meanwhile eNOS always expressed at a low level. CONCLUSION： The injury and phenotype shift of SECs is a oathological basis in the develolpment of portal hypertension of DMN- induced liver cirrhosis in rats. Imbalance of ET- 1 and NO production increases intrahepatic resistance, which plays an important＇ role in the development of portal hypertension.

关 键 词：大鼠 肝硬化 一氧化氮 内皮缩血管肽类 高血压 门静脉 

分 类 号：R363[医药卫生—病理学]