肝纤维化发生机制研究新进展*

doi:10.3969/j.issn.1672-5069.2016.01.035

摘要/Abstract

摘要： 肝纤维化是一种肝内弥漫性细胞外基质（ECM）过度沉积的病理过程,是多种慢性肝脏疾病进展为肝硬化的共同反应。ECM主要来源于肝星状细胞（HSC）,且HSC的激活是肝纤维化发生发展的中心环节。本文主要探讨了HSC的激活机制在肝纤维化发生过程中的作用,并结合肝实质细胞、其他非实质细胞以及各种促纤维化因子的作用对肝纤维化的发生机制进行了总结。本文还阐述了肠道菌群失调和微小RNA的异常表达在肝纤维化发生中的意义。

关键词: 肝纤维化, 发生机制, 细胞外基质, 肠道菌群失调, 微小RNA

Abstract: Liver fibrosis is a pathological process characterized by intrahepatic diffuse excess deposition of extracellular matrix （ECM）,which is also a common response occurred in the progression of varied chronic liver disease to cirrhosis. As ECM is mainly secreted by hepatic stellate cells（HSC） and its activation process is the central part of liver fibrosis development. In this review,we will summarize the mechanism of HSC activation in combination with the roles of hepatocytes,other non-parenchymal cells and various profibrogenic cytokines. This paper will also describe the significance of intestinal flora alteration and aberrant expression of microRNAs in the development of liver fibrosis.

Key words: Liver fibrosis, Pathogenesis, Hepatic stellate cell, Extracellular matrix, Intestinal flora alteration, MicroRNAs

陈宵瑜综述, 杨长青审校. 肝纤维化发生机制研究新进展^*[J]. 实用肝脏病杂志, 2016, 19(1): 121-124.

Chen Xiaoyu, Yang Changqing. Progress in the pathogenesis of liver fibrosis[J]. JOURNAL OF PRACTICAL HEPATOLOGY, 2016, 19(1): 121-124.

参考文献

[1] 汪美凤,平键. 肝星状细胞主要信号转导通路与肝纤维化的关系. 实用肝脏病杂志,2010,13（6）:466-469.
[2] Sohrabpour AA,Mohamadnejad M,Malekzadeh R. Review article:the reversibility of cirrhosis. Aliment Pharmacol Ther,2012, 36（9）:824-832.
[3] Novo E. Hepatic myofibroblasts:a heterogeneous population of multifunctional cells in liver fibrogenesis. Int J Biochem Cell Biol,2009,41（11）:2089-2093.
[4] Okuno M.Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells. Hepatology, 1997,26（4）:913-921.
[5] Parsons CJ,Takashima M,Rippe RA. Molecular mechanisms of hepatic fibrogenesis. J Gastroenterol Hepatol,2007,22（Suppl 1）:S79-84.
[6] Friedman SL. Hepatic stellate cells:protean,multifunctional,and enigmatic cells of the liver. Physiol Rev,2008,88（1）:125-172.
[7] Milani S.In situ hybridization for procollagen types I,III and IV mRNA in normal and fibrotic rat liver:evidence for predominant expression in nonparenchymal liver cells. Hepatology,1989,10（1）:84-92.
[8] 齐海宇,孙芳芳,阴赪宏. 肝纤维化的病因及其发病机制. 中国医刊,2011,46（7）:12-14.
[9] Guo J,Friedman SL. Hepatic fibrogenesis. Semin Liver Dis, 2007,27（4）:413-426.
[10] Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology,2008,134（6）:1655-1669.
[11] Woessner JF. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J,1991,5（8）:2145-2154.
[12] Milani S. Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol,1994,144（3）:528-537.
[13] Marra F. Phosphatidylinositol 3-kinase is required for platelet-derived growth factor's actions on hepatic stellate cells. Gastroenterology,1997,112（4）:1297-1306.
[14] Shin HW.Transcriptional profiling and Wnt signaling activation in proliferation of human hepatic stellate cells induced by PDGF-BB. Korean J Hepatol,2009,15（4）:486-495.
[15] Pinzani M. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology,1996,110（2）:534-548.
[16] Wu XL. Effect of oxymatrine on the TGFbeta-Smad signaling pathway in rats with CCl4-induced hepatic fibrosis. World J Gastroenterol,2008,14（13）:2100-2105.
[17] Liang TJ. Effect of ursodeoxycholic acid on TGF beta1/Smad signaling pathway in rat hepatic stellate cells. Chin Med J （Engl）,2009,122（10）:1209-1213.
[18] Schmidt MV,Brune B,von Knethen A. The nuclear hormone receptor PPARgamma as a therapeutic target in major diseases. Sci World J,2010,10:2181-2197.
[19] Gervois P. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med,2000,38（1）:3-11.
[20] Duez H,Fruchart JC,Staels B. PPARS in inflammation, atherosclerosis and thrombosis. J Cardiovasc Risk,2001,8（4）: 187-194.
[21] 成扬,平键,徐列明. 姜黄素上调PPAR_抑制肝星状细胞活化标志表达的研究. 中国实用内科学杂志,2006,9（24）:1937-1940.
[22] 成扬,平键,刘成.姜黄素激活过氧化物酶体增殖因子活化受体γ信号对大鼠星状细胞基质金属蛋白酶2、9活性和胞核核因子-κBp65表达的影响. 中国中西医结合杂志,2007,27（5）: 433-439.
[23] Cheng Y,Ping J,Xu LM. Effects of curcumin on peroxisome proliferator-activated receptor gamma expression and nuclear translocation/redistribution in culture-activated rat hepatic stellate cells. Chin Med J （Engl）,2007,120（9）:794-801.
[24] Suresh Y,Das UN. Leptin-the fat controller. J Assoc Physicians India,1998,46（6）:538-544.
[25] Conde J. At the crossroad between immunity and metabolism: focus on leptin. Expert Rev Clin Immunol,2010,6（5）:801-808.
[26] Vansaun MN. Molecular pathways:adiponectin and leptin signaling in cancer. Clin Cancer Res,2013,19（8）:1926-1932.
[27] Friedman SL. Mechanisms of disease:Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol,2004,1（2）:98-105.
[28] Wang J. Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology,2009,137（2）:713-723.
[29 何云. 非实质肝细胞在肝纤维化发生机制中的作用. 实用肝脏病杂志,2000,5（2）:122-124.
[30] 涂传涛,王吉耀. 肝纤维化的细胞分子机制研究进展. 中华肝脏病杂志,2014,22（1）:5-8.
[31] 朱永红,聂青和. 肝纤维化发生机制的研究进展. 实用肝脏病杂志,1998,3（3）:189-191.
[32] Mentink-Kane MM. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin（IL）-10,IL-12p40,and IL-13Ralpha2. Gastroenterology,2011,141（6）:2200-2209.
[33] Tu CT. Glycyrrhizin regulates CD4+T cell response during liver fibrogenesis via JNK,ERK and PI3K/AKT pathway. Int Immunopharmacol,2012,14（4）:410-421.
[34] 陈肯,康权. 上皮间质转化与肝纤维化的研究进展. 世界华人消化杂志,2012,20（11）:941-945.
[35] Zeisberg M. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem,2007,282（32）:23337-23347.
[36] Kaimori A.Transforming growth factor-beta1 induces an epithelial-to-mesenchymal transition state in mouse hepatocytes in vitro. J Biol Chem,2007,282（30）:22089-22101.
[37] Rygiel KA. T cell-mediated biliary epithelial-to-mesenchymal transition in liver allograft rejection. Liver Transpl,2010,16（5）: 567-576.
[39] Feng XH,Derynck R. Specificity and versatility in TGF-beta signaling through Smads. Annu Rev Cell Dev Biol,2005,21: 659-693.
[40] Zavadil J,Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene,2005,24（37）:5764-5774.
[41] 翟齐啸,田丰伟,王刚,等. 肠道微生物与人体健康的研究进展. 食品科学,2013,34（15）:337-341.
[42] Seo YS,Shah VH. The role of gut-liver axis in the pathogenesis of liver cirrhosis and portal hypertension. Clin Mol Hepatol,2012,18（4）:337-346.
[43] Seki E,Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology,2008,48（1）:322-335.
[44] 秦庆福,李洪福. 慢性肝病与肠道菌群的研究进展. 中国微生态学杂志,2012,24（5）:476-477.
[45] 赵龙凤,李红,韩德五. 肠源性内毒素血症与肝病. 世界华人消化杂志,2000,8（10）:1248.
[46] Lopez E. Clinical and technical phosphoproteomic research. Proteome Sci,2011,9:27.
[47] Nibbe RK,Chance MR. Approaches to biomarkers in human colorectal cancer:looking back,to go forward. Biomark Med,2009,3（4）:385-396.
[48] Gunnarsdottir SA.Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension. Am J Gastroenterol,2003,98（6）:1362-1370.
[49] 王玲.肠道菌群改变与肝纤维化相互作用的研究进展. 世界华人消化杂志,2014,22（26）:3937-3940.
[50] Nilsen TW. Mechanisms of microRNA-mediated gene regulation in animal cells. Trends Genet,2007,23（5）:243-249.
[51] Marquez RT. Correlation between microRNA expression levels and clinical parameters associated with chronic hepatitis C viral infection in humans. Lab Invest,2010,90（12）:1727-1736.
[52] Roderburg C. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology,2011,53（1）: 209-218.
[53] Kwiecinski M. Hepatocyte growth factor （HGF） inhibits collagen I and IV synthesis in hepatic stellate cells by miRNA-29 induction. PLoS One,2011,6（9）:e24568.
[54] Szabo G,Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol,2013,10（9）:542-552.
[55] 周雄根,舒建昌. 微小RNA与肝纤维化关系的研究进展. 广东医学,2011,32（24）:3280-3283.

肝纤维化发生机制研究新进展^*

Progress in the pathogenesis of liver fibrosis

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