HIV感染肝星状细胞促进肝纤维化实验研究——HIV/HCV合并感染快速肝纤维化机制探讨  

Study on liver fibrosis promoted by HIV-infected human hepatic stellate cells——Mechanism of accelerated fibrosis in HIV/HCV coinfected patients

作　　者：洪丰[1,2] 司传平[2] 石军[3] 曾晓立[4] 

机构地区：[1]济宁医学院附属济宁市第一人民医院,山东济宁272011 [2]济宁医学院教务处,济宁272067 [3]山东省立医院,山东济南250021 [4]济宁医学院科研处,济宁272067

出　　处：《济宁医学院学报》2012年第4期230-234,250,共6页Journal of Jining Medical University

基　　金：国家自然科学基金项目(编号:81170395)

摘　　要：目的 HIV/HCV合并感染较单纯HCV感染患者肝纤维化发展迅速,肝病死亡率高。肝纤维化进程与HIV RNA水平相关,提示HIV在肝纤维化形成中起重要作用。然而,HIV通过HSC促进肝纤维化作用知之甚少。本文就HIVⅢB能否感染HSC、HIV/HIVgp120促进HSC活化和Ⅰ型胶原蛋白表达及其相关细胞信号通路进行了检测。方法以HIVⅢB感染和gp120刺激原代人HSCS后,采用ELISA、qRT-PCR和Western Blot对感染结果和纤维化发生有关标志物进行分析,并以shRNA和uo126预处理HSC封闭CXCR4及其下游因子ERK,进一步评估CXCR4-ERK细胞信号系统在HIV诱导肝纤维化中的作用。结果 HIVⅢB能感染培养的人HSCS并促其表达Ⅰ型胶原蛋白。gp120同样可刺激HSC表达Ⅰ型胶原蛋白和肌动蛋白。当CXCR4及/或ERK被抑制后,HIV和gp120的上述作用明显降低。结论本研究表明,HIV/HIVgp120通过诱导HSC生物学功能促进肝纤维化,CXCR4-ERK细胞转导通路是主要机制之一。Objective HIV/HCV coinfection develop more rapid hepatic fibrosis and liver death than those infected with HCV only.In HIV/HCV-coinfected patients,fibrosis progression correlates with HIV RNA levels,suggesting an important role of HIV in liver fibrogenesis.While activated hepatic stellate cells（HSCs） express CXCR4,one of major HIV chemokine coreceptors.However,little is known about the profibrogenic role of HIV on hepatic stellate cells.We therefore examined the impact of HIV/HIV gp120 on HSC activation,collagen I expression,and underlying signaling pathways in vitro.Methods Primary human HSCs were infected with HIV IIIB and treated with X4 gp120 and expression of fibrogenic markers assessed by ELISA,qRT-PCR and Western blot.CXCR4 and its downstream intracellular signaling pathways were evaluated with Western blot and pre-treatment with CXCR4-targeted shRNA or ERK inhibitor.Results HIV-IIIB（CXCR4-tropic） could infect primary human HSCs and promot HSC collagen I expression.Gp120 significantly aslo increased expression of α-smooth muscle actin（α-SMA） and collagen I in HSCs which was blocked by pre-incubation with CXCR4-targeted shRNA.Furthermore,Gp120 promoted extracellular signal-regulated kinase（ERK） 1/2 phosphorylation and pretreatment with an ERK inhibitor attenuated HSC activation and collagen I expression.Conclusion Our data indicate a potential role of HIV/HIV gp120 in liver fibrosis mediated the effects on HSCs and the regulation occurs in a CXCR4-dependent fashion.

关 键 词：HIV/HCV合并感染 肝纤维化 肝星状细胞 CXCR4受体 

分 类 号：R575[医药卫生—消化系统]