原发性胆汁性肝硬化患者肝组织转化生长因子β-1表达水平变化

doi:10.3969/j.issn.1672-5069.2018.02.020

摘要/Abstract

摘要： 目的探讨原发性胆汁性肝硬化（PBC）患者肝组织转化生长因子-β1（TGF-β1）表达的变化。方法 52例PBC患者接受超声引导下肝穿刺活检,选择病理科留取的正常肝组织20份作为对照,另选择20例健康人采集静脉血。采用免疫组化法检测肝组织TGFβ-1表达,采用ELISA法检测血清肿瘤坏死因子α（TNF-α）和白介素6（IL-6）水平。结果正常肝组织不表达或仅有少量TGF-β1表达,而PBC患者肝实质细胞胞浆内呈TGF-β1高表达;PBC患者血清TNF-α和IL-6水平分别为（28.71±13.54） pg/ml和（21.3±9.4） pg/ml,显著高于健康人【分别为（21.3±15.4） pg/ml和（2.1±1.6） pg/ml,P<0.01】;7例PBC肝组织肝纤维化S0期患者肝组织TGF-β1表达及血清TNF-α和IL-6水平分别为（0.5±0.2）10-2、（7.1±4.1） pg/ml和（5.1±1.0） pg/ml,显著低于12例S1期【（4.2±1.3） 10-2、（18.6±6.2） pg/ml、（11.5±3.6） pg/ml,P<0.01】、18例S2期【（6.9±1.2） 10-2、（27.3±9.9） pg/ml、（19.4±4.1） pg/ml,P<0.01】、9例S3期【（13.3±15.1） 10-2、（39.7±15.18） pg/ml、（27.3±8.1） pg/ml,P<0.01】和6例S4期【（21.2±17.1） 10-2、（53.4±17.3） pg/ml、（47.8±11.0） pg/ml,P<0.01】;15例Child-Pugh A级患者肝组织TGF-β1表达及血清TNF-α和IL-6水平分别为（1.9±1.6） 10-2、（12.2±3.1） pg/ml和（7.3±2.5） pg/ml,显著低于25例Child-Pugh B级【（15.9±13.6） 10-2、（32.9±8.6） pg/ml、（21.8±6.3） pg/ml,P<0.01】或12例C级患者【（22.6±18.5） 10-2、（49.1±19.3） pg/ml、（45.5±12.7） pg/ml,P<0.01】。结论 PBC患者肝组织TGFβ-1表达及血清TNF-α和IL-6水平显著升高,可能与肝组织纤维化增生和/或肝功能受损有关。

关键词: 原发性胆汁性肝硬化, 肝纤维化, 转化生长因子β, -1, 肿瘤坏死因子α, 白介素6

Abstract: Objective To investigate the expression of transforming growth factor β-1（TGFβ-1） in liver tissues of patients with primary biliary cirrhosis（PBC） and its relationship with liver fibrosis. Methods 52 patients with PBC and 20 healthy persons were recruited in our hospital. The patients with PBC received liver biopsies and 20 normal liver tissues from the Department of Pathology in our hospital served as control. The expression of TGFβ-1 in liver tissues was detected immunohistochemistry and serum tumor necrosis factor α（TNF-α） and interleukin 6（IL-6） levels were detected by ELISA. Results TGFβ-1 was not expressed or little expressed in normal liver tissues,while it was highly expressed in cytoplasm of hepatic parenchyma cells in patients with PBC;serum TNF-α and IL-6 levels in patients with PBC were （28.71±13.54） pg/ml and （21.3±9.4） pg/ml,significantly higher than those in control group[（21.3±15.4） pg/ml and （2.1±1.6） pg/ml,respectively,P<0.01];The expression level of TGFβ-1 in liver tissues and serum levels of TNF-α and IL-6 in 7 patients with PBC with liver fibrosis stage S0 were（0.5±0.2） 10-2,（7.1±4.1） pg/ml and（5.1±1.0） pg/ml,significantly lower than those in 12 with stage S1 [（4.2±1.3） 10-2,（18.6±6.2） pg/ml and （11.5±3.6） pg/ml,P<0.01],or in 18 with stage S2 [（6.9±1.2） 10-2,（27.3±9.9） pg/ml and （19.4±4.1） pg/ml,P<0.01],or in 9 with stage S3[（13.3±15.1） 10-2,（39.7±15.18） pg/ml and（27.3±8.1） pg/ml,P<0.01] or in 6 with stage S4 [（21.2±17.1） 10-2,（53.4±17.3） pg/ml,（47.8±11） pg/ ml, respectively,P<0.01];the expression level of TGFβ-1 in liver tissues and serum levels of TNF-α and IL-6 in 15 patients with Child-Pugh class A were（1.9±1.6） 10-2,（12.2±3.1） pg/ml and（7.3±2.5） pg/ml,significantly lower than [（15.9±13.6） 10-2,（32.9±8.6） pg/ml an（21.8±6.3） pg/ml,P<0.01）] in 25 patients with Child-Pugh class B or [（22.6±18.5） 10-2,（49.1±19.3） pg/ml and（45.5±12.7） pg/ml,P<0.01] in 12 patients with Child-Pugh class C. Conclusion The expression of TGFβ-1 in liver tissues and serum TNF-α and IL-6 levels increase in patients with PBC,which might be related to the formation of liver fibrosis and the deteriorated liver function.

Key words: Primary biliary cirrhosis, Liver fibrosis, Transforming growth factor β-1;, Tumor necrosis factor α, Interleukin 6

秦维, 陈宇萍, 杨昭, 祝素平, 霍玉玲, 李木松. 原发性胆汁性肝硬化患者肝组织转化生长因子β-1表达水平变化[J]. 实用肝脏病杂志, 2018, 21(2): 237-240.

Qin Wei, Chen Yuping, Yang Zhao, et al. Expression of transforming growth factor β-1 in liver tissues of patients with primary biliary cirrhosis and its relationship with liver fibrosis[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2018, 21(2): 237-240.

参考文献

[1] Floreani A,Franceschet I,Cazzagon N,et al.Extrahepatic autoimmune conditions are associated with primary biliary cirrhosis. Clin Rev Aller Immunol,2015,48(3):192-197.
[2] 李萍英,陆伦根. 原发性胆汁性肝硬化药物治疗进展. 实用肝脏病杂志,2015,18(4):441-444.
[3] Park JH,Yoon J.Schizandrin inhibits fibrosis and epithelial-mesenchymal transition in transforming growth factor-β1-stimulated AML12 cells.Int Immunopharmacol,2015,25(2):276-284.
[4] Falasca K,Reale M,Ucciferri C,et al.Cytokines,hepatic fibrosis and antiretroviral therapy role in neurocognitive disorders HIV-related.Aids Res Human Retrovir,2016,33(3):246-253.
[5] 中华医学会肝病学分会、消化病学分会、感染病学分会. 胆汁淤积性肝病诊断和治疗共识(2015). 实用肝脏病杂志,2016,19(6):Ⅰ-ⅩⅠ.
[6] Chen YX,Huang YH,Zheng WD,et al.Interleukin-10 gene modification attenuates hepatocyte activation of rat hepatic stellate cells in vitro. Mol Med Rep,2013,7(2):371-378.
[7] 黄文琪,许金超,闵峰,等. 吲哚菁绿清除试验对肝硬化患者肝脏储备功能的评估价值. 实用肝脏病杂志,2015,18(5):468-471.
[8] Park SA,Kim MJ,Park SY,et al.EW-7197 inhibits hepatic,renal,and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling.Cell Mol Lif Sci,2015,72(10):2023-2023.
[9] Park HJ,Kim HG,Wang JH,et al.Comparison of TGF-β,PDGF,and CTGF in hepatic fibrosis models using DMN,CCl4,and TAA. Drug Chem Toxicol,2016,39(1):111-118.
[10] 曾波,李彦.慢性乙型肝炎和肝硬化患者血清骨桥蛋白和TGF-β1水平变化. 实用肝脏病杂志,2017,20(2):240-241.
[11] Wermuth PJ,Li Z,Mendoza FA,et al.Stimulation of transforming growth factor-β1-induced endothelial-to-mesenchymal transition and tissue fibrosis by endothelin-1(ET-1):a novel profibrotic effect of ET-1. Plos One,2016,11(9):e0161988-e0161988.
[12] Liu B,Zhang X,Zhang FC,et al.Aberrant TGF-β1 signaling contributes to the development of primary biliary cirrhosis in murine model.World J Gastroenterol,2013,9(35):5828-5836.
[13] Sant'Anna LB, Hage R,Cardoso MA,et al. Anti-fibrotic effects of human amniotic membrane transplantation in established biliary fibrosis induced in rats. Cell Transplant,2016,25(12):2245-2257.
[14] Meng F,Wang K,Aoyama T,et al.Interleukin-17 signaling in inflammatory,Kupffer cells,and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology,2012,143(3):765-776.
[15] 贾玉杰,赵芳,张彩华,等. 中药肝复康对TNF-α介导的炎症性肝损伤和大鼠肝纤维化的抑制作用.中国微生态学杂志,2016,28(2):146-150.
[16] 薛如意,张丹瑛,吴昊,等. Toll样受体3基因缺陷促进四氯化碳诱导的小鼠肝纤维化损伤. 中国临床医学,2016,23(1):1-5.
[17] Salter ML,Lau B,Mehta SH,et al.Correlates of elevated interleukin-6 and C-reactive protein in persons with or at high risk for HCV and HIV infections. J Acquir Immune Defic Syndr,2013,64(5):488-95.
[18] 李衍飞,邵军,王志鑫,等.泡球蚴囊液对大鼠肝星状细胞TGF-β1、IL-6及TNF-α表达的影响.中国普外基础与临床杂志,2016,23(12):1500-1502.
[19] Oertelt S,Lian ZX,Cheng CM,et al.Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol,2006,177(3):1655-60.
[20] Nawaz R,Zahid S,Idrees M,et al.HCV-induced regulatory alterations of IL-1β,IL-6,TNF-α,operative,leading liver en-route to non-alcoholic steatohepatitis. Inflamm Res,2017,66(6):477-486.