血管紧张素Ⅱ1型受体在乙型肝炎病毒感染者肝纤维化形成过程中的表达变化及意义

Significance and expression of angiotensin Ⅱ type 1 receptor in process of hepatic fibrosis in HBV-infected cases

目的研究血管紧张素Ⅱ1型受体(AT1R)在不同阶段慢性肝病患者肝组织的表达情况,探讨血管紧张素Ⅱ(AngiotensinⅡ,AngⅡ)转换酶抑制剂(ACEIs)及血管紧张素Ⅱ受体阻滞剂(ARBs)治疗肝纤维化的可能性。通过定量检测血清乙型肝炎病毒DNA(HBV DNA),探讨HBV病毒载量与肝纤维化分期的关系。方法以2007年1月至2008年1月因慢性HBV感染行肝组织穿刺术或手术切除的肝组织标本55例,正常肝组织12例(正常对照组)为研究对象,分别进行病理分级。并根据慢性肝炎的纤维化分期标准,将入选病例分为:S0-1组、S2-4组、晚期肝硬化组及正常对照组。67例均在肝穿或手术前后2日内抽取空腹静脉血4 ml并分离血清。用免疫组织化学法及逆转录聚合酶链反应(RT-PCR)法检测肝组织中AT1R及AT1R mRNA的表达。用荧光定量PCR法对血清HBV DNA进行定量检测。结果 AT1R及AT1RmRNA在正常肝组织中只微弱表达或不表达,而随纤维化分期的加重其表达量逐渐增加。与正常对照组比较,各组肝组织中AT1R的阳性表达均增多(平均秩为21.91,41.28,53.12 vs 15.25,H=34.005,P<0.01),S0-1组与正常对照组比较差异无统计学意义(P>0.05),余组间比较差异均有统计学意义(P<0.01或P<0.05)。AT1RmRNA的表达正常对照组为0.173±0.036,S0-1组0.196±0.045,S2-4组0.394±0.098,晚期肝硬化组0.603±0.116。S0-1组与正常对照组比较纤维化有加重趋势,但差异无统计学意义(P>0.05),余组间比较差异均有统计学意义(P<0.01或P<0.05)。血清HBV DNA含量与肝组织纤维化分期之间无相关性(P>0.05)。结论 AT1R及AT1RmRNA在正常肝组织中只微弱表达或不表达,在纤维化及硬化肝组织中表达高度上调,且其表达强度与纤维化分期密切相关。从而认为肾素血管紧张素系统(RAS系统)的AngⅡ及AT1R在肝纤维化发生发展过程中起了重要作用。血清HBV DNA含量与肝组织纤维化分期之间无明显关系。

Objective To explore the angiotensin Ⅱ （Ang Ⅱ ） type 1 receptor（ATIR） and mRNA＇s expression at different stages of type B virus chronic hepatitis, from the state of type B virus carriers to different stages of hepatic cirrhosis,providing informations of probability of angiotensin-converting enzyme inhibitors（ACEIs） and Ang Ⅱ type 1 receptor bloekers（ARBs） in treating liver fibrosis. This clinic study explored the relationship between serum hepatitis virus type B （HBV） DNA and liver fibrosis. Methods Sixty-seven cases in total were enrolled in the study and pathologically classified. Among 67 cases, 55 were liver biopsy specimens by liver punctures or liver operations from January 2007 to January 2008 because of chronic hepatitis B virus infection,and the other 12 cases were normal liver tissue in the same period. According to the diagnostic criteria of chronic hepatitis and fibrosis stages, the selected cases were divided into four groups： S0-1 group, S2-4 group, end stage of cirrhosis group and normal control group. Four milliliters of fast serum samples from the 67 cases were obtained 2 days around liver biopsy or surgery. The expressions of AT1R and AT1RmRNA in liver tissue were examined by immunohistochemistry and reverse transcription polymerase chain reaction（RT-PCR） respectively. Serum HBV DNA was quantitatively detected with fluorescence quantitative PCR. Results AT1R and AT1RmRNA were weak or no expressions in the normal controls,but they were increasingly expressed in fibrotic and cirrhotic tissues closely related to fibrosis stages. Expressions of ATIR in the other groups were significantly increased as compared to that of normal control group（mean rank 21.91,41.28,53.12 vs 15.25, H 34. 005, P d0.01）, there were no statistic differences between S0-1 group and normal control group（ P〈0.05） ,and there were statistic differences between the other groups （ P〈0.01 or P 〈0.05）. Expressions of ATIR mRNA in normal control group,S0-1 ,S2-4 and end stage of cirrhosis group were 0. 173±0. 036,0. 196±0. 045,0. 394± 0. 098,0. 603±0. 116. S0-1 group and normal control group were no significant difference（ P 〉0.05） ,and there were statistic differences between the other groups （ P〈0.01 or P d0.05）. There was no correlation between HBV DNA level and liver fibrosis stage（ P 〉0.05）. Conclusion AT1R and ATIRmRNA are weak or no expression in normal liver tissue,but their expressions are increasing in the fibrosis and cirrhosis, and the intensity of the expressions is closely related to fibrosis stage. So Ang Ⅱ and AT1R in renin-angiotensin system （RAS） play an important role in the development of liver fibrosis. There is no correlation between HBV DNA level and liver fibrosis stage.