肝内胆管改变与肝纤维化的关系

尤文铮; 任万雷; 宣世英; 胡豆豆

doi:10.3969/j.issn.1001-5256.2022.01.032

肝内胆管改变与肝纤维化的关系

DOI: 10.3969/j.issn.1001-5256.2022.01.032

尤文铮¹,
任万雷²,
宣世英^1, ,,
胡豆豆^{1, 3, ,}

1.
南京医科大学附属青岛临床医学院，山东青岛 266011
2.
青岛大学附属青岛市中心医院中医一科，山东青岛 266042
3.
青岛市市立医院消化内二科，山东青岛 266011

基金项目:

国家自然科学基金青年科学基金项目 (81800543)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：尤文铮负责撰写修改论文; 任万雷负责参与文献的收集、整理; 宣世英、胡豆豆负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
宣世英，xuansydxy@163.com

胡豆豆，hudoudou1984@163.com

计量
- 文章访问数: 521
- HTML全文浏览量: 101
- PDF下载量: 80
- 被引次数: 0
出版历程
- 收稿日期: 2021-05-18
- 录用日期: 2021-06-11
- 出版日期: 2022-01-20

Association between intrahepatic bile duct alterations and liver fibrosis

Wenzheng YOU¹,
Wanlei REN²,
Shiying XUAN^{1
, ,},
Doudou HU^{1, 3
, ,}

1.
Qingdao Clinical Medical College Affiliated to Nanjing Medical University, Qingdao, Shandong 266011, China
2.
First Department of Traditional Chinese Medicine, Qingdao Central Hospital Affiliated to Qingdao University, Qingdao, Shandong 266042, China
3.
Second Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, Shandong 266011, China

Research funding:

Youth Science Fund Project by National Natural Science Foundation of China (81800543)

摘要

摘要: 肝硬化是由多种原因引起的以弥漫性纤维组织增生、肝小叶结构破坏、假小叶形成为特征的肝病。在多种肝硬化动物模型及不同病因肝硬化患者中均可见胆管增生。多种神经肽、神经递质及激素等调节因子参与的信号通路调控胆管增生。增生的胆管通过介导星状细胞增殖、活化，促进肝纤维化的形成。总结了肝硬化时肝内胆管系统的改变及其对纤维化进程的影响，胆管细胞增生与肝纤维化相关的信号通路，以及胆管结构的动态演变对肝纤维化程度的预测价值。提出胆管增生可能成为干预肝纤维化的潜在靶点，为早期治疗及逆转肝纤维化提供新的思路和方法。
- 肝硬化 /
- 胆管, 肝内 /
- 病理过程
Abstract: Liver cirrhosis is a liver disease caused by various factors and is characterized by diffuse fibrous hyperplasia, lobular structural damage, and pseudolobule formation. Bile duct proliferation has been observed in a variety of animal models of liver cirrhosis and patients with liver cirrhosis caused by different etiologies, and it is regulated by signaling pathways with the involvement of multiple regulatory factors such as neuropeptides, neurotransmitters, and hormones. Moreover, the proliferated bile ducts promote the formation of liver fibrosis by mediating the proliferation and activation of hepatic stellate cells. This article summarizes the changes of the intrahepatic bile duct system in liver cirrhosis and its influence on the process of liver fibrosis, various signaling pathways associated with cholangiocyte proliferation and liver fibrosis, and the value of the dynamic evolution of bile duct structure in predicting the degree of liver fibrosis. It is pointed out that bile duct proliferation may become a potential target for the intervention of liver fibrosis, which provides new ideas and methods for early treatment and reversal of liver fibrosis.
- Liver Cirrhosis /
- Bile Ducts, Intrahepatic /
- Pathologic Processes

HTML全文

参考文献(37)

[1]	GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017[J]. Lancet, 2020, 5(3): 245-266. DOI: 10.1016/S2468-1253(19)30349-8.
[2]	LI H. Angiogenesis in the progression from liver fibrosis to cirrhosis and hepatocelluar carcinoma[J]. Expert Rev Gastroenterol Hepatol, 2021, 15(3): 217-233. DOI: 10.1080/17474124.2021.1842732.
[3]	NGUYEN T, TANG W, NAN L, et al. The role of bile duct reactive change in the pathogenesis of liver fibrosis due to hepatitis C[J]. Exp Mol Pathol, 2005, 79(2): 95-99. DOI: 10.1016/j.yexmp.2005.04.010.
[4]	RICHARDSON MM, JONSSON JR, POWELL EE, et al. Progressive fibrosis in nonalcoholic steatohepatitis: Association with altered regeneration and a ductular reaction[J]. Gastroenterology, 2007, 133(1): 80-90. DOI: 10.1053/j.gastro.2007.05.012.
[5]	RÓKUSZ A, VERES D, SZVCS A, et al. Ductular reaction correlates with fibrogenesis but does not contribute to liver regeneration in experimental fibrosis models[J]. PLoS One, 2017, 12(4): e0176518. DOI: 10.1371/journal.pone.0176518.
[6]	LV WJ, ZHAO XY, HU DD, et al. Insight into bile duct reaction to obstruction from a three-dimensional perspective using ex vivo phase-contrast CT[J]. Radiology, 2021, 299(3): 597-610. DOI: 10.1148/radiol.2021203967.
[7]	SVEGLIATI-BARONI G, FARACI G, FABRIS L, et al. Insulin resistance and necroinflammation drives ductular reaction and epithelial-mesenchymal transition in chronic hepatitis C[J]. Gut, 2011, 60(1): 108-115. DOI: 10.1136/gut.2010.219741.
[8]	WOOD MJ, GADD VL, POWELL LW, et al. Ductular reaction in hereditary hemochromatosis: The link between hepatocyte senescence and fibrosis progression[J]. Hepatology, 2014, 59(3): 848-857. DOI: 10.1002/hep.26706.
[9]	QIN L, ZHAO X, JIAN J, et al. High-resolution 3D visualization of ductular proliferation of bile duct ligation-induced liver fibrosis in rats using X-ray phase contrast computed tomography[J]. Sci Rep, 2017, 7(1): 4215. DOI: 10.1038/s41598-017-03993-2.
[10]	MILANI S, HERBST H, SCHUPPAN D, et al. Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis[J]. Gastroenterology, 1990, 98(1): 175-184. DOI: 10.1016/0016-5085(90)91307-r.
[11]	CLOUSTON AD, POWELL EE, WALSH MJ, et al. Fibrosis correlates with a ductular reaction in hepatitis C: Roles of impaired replication, progenitor cells and steatosis[J]. Hepatology, 2005, 41(4): 809-818. DOI: 10.1002/hep.20650.
[12]	GOUW AS, CLOUSTON AD, THEISE ND. Ductular reactions in human liver: Diversity at the interface[J]. Hepatology, 2011, 54(5): 1853-1863. DOI: 10.1002/hep.24613.
[13]	HUBEL E, SAROHA A, PARK WJ, et al. Sortilin deficiency reduces ductular reaction, hepatocyte apoptosis, and liver fibrosis in cholestatic-induced liver injury[J]. Am J Pathol, 2017, 187(1): 122-133. DOI: 10.1016/j.ajpath.2016.09.005.
[14]	HALL C, SATO K, WU N, et al. Regulators of cholangiocyte proliferation[J]. Gene Expr, 2017, 17(2): 155-171. DOI: 10.3727/105221616X692568.
[15]	FABRIS L, BRIVIO S, CADAMURO M, et al. Revisiting epithelial-to-mesenchymal transition in liver fibrosis: Clues for a better understanding of the "reactive" biliary epithelial phenotype[J]. Stem Cells Int, 2016, 2016: 2953727. DOI: 10.1155/2016/2953727.
[16]	MASYUK TV, RITMAN EL, LARUSSO NF. Hepatic artery and portal vein remodeling in rat liver: Vascular response to selective cholangiocyte proliferation[J]. Am J Pathol, 2003, 162(4): 1175-1182. DOI: 10.1016/S0002-9440(10)63913-2.
[17]	MCMILLIN M, DEMORROW S, GLASER S, et al. Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats[J]. Am J Physiol Gastrointest Liver Physiol, 2017, 313(5): G410-G418. DOI: 10.1152/ajpgi.00421.2016.
[18]	SATO K, MENG F, GIANG T, et al. Mechanisms of cholangiocyte responses to injury[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1262-1269. DOI: 10.1016/j.bbadis.2017.06.017.
[19]	GLASER SS, GAUDIO E, MILLER T, et al. Cholangiocyte proliferation and liver fibrosis[J]. Expert Rev Mol Med, 2009, 11: e7. DOI: 10.1017/S1462399409000994.
[20]	POLAK JM, COULLING I, BLOOM S, et al. Immunofluorescent localization of secretin and enteroglucagon in human intestinal mucosa[J]. Scand J Gastroenterol, 1971, 6(8): 739-744. DOI: 10.3109/00365527109179946.
[21]	ALPINI G, ROBERTS S, KUNTZ SM, et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver[J]. Gastroenterology, 1996, 110(5): 1636-1643. DOI: 10.1053/gast.1996.v110.pm8613073.
[22]	GLASER S, LAM IP, FRANCHITTO A, et al. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation[J]. Hepatology, 2010, 52(1): 204-214. DOI: 10.1002/hep.23657.
[23]	GLASER S, MENG F, HAN Y, et al. Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice[J]. Gastroenterology, 2014, 146(7): 1795-1808. e12. DOI: 10.1053/j.gastro.2014.02.030.
[24]	WU N, MENG F, INVERNIZZI P, et al. The secretin/secretin receptor axis modulates liver fibrosis through changes in transforming growth factor-β1 biliary secretion in mice[J]. Hepatology, 2016, 64(3): 865-879. DOI: 10.1002/hep.28622.
[25]	GUERRIER M, ATTILI F, ALPINI G, et al. Prolonged administration of secretin to normal rats increases biliary proliferation and secretin-induced ductal secretory activity[J]. Hepatobiliary Surg Nutr, 2014, 3(3): 118-125. DOI: 10.3978/j.issn.2304-3881.2014.04.04.
[26]	KENNEDY L, FRANCIS H, INVERNIZZI P, et al. Secretin/secretin receptor signaling mediates biliary damage and liver fibrosis in early-stage primary biliary cholangitis[J]. FASEB J, 2019, 33(9): 10269-10279. DOI: 10.1096/fj.201802606R.
[27]	NISHIO T, HU R, KOYAMA Y, et al. Activated hepatic stellate cells and portal fibroblasts contribute to cholestatic liver fibrosis in MDR2 knockout mice[J]. J Hepatol, 2019, 71(3): 573-585. DOI: 10.1016/j.jhep.2019.04.012.
[28]	SPITSIN S, PAPPA V, DOUGLAS SD. Truncation of neurokinin-1 receptor-Negative regulation of substance P signaling[J]. J Leukoc Biol, 2018, 103(6): 1043-1051. DOI: 10.1002/JLB.3MIR0817-348R.
[29]	CECI L, FRANCIS H, ZHOU T, et al. Knockout of the tachykinin receptor 1 in the Mdr2^-/- (Abcb4^-/-) mouse model of primary sclerosing cholangitis reduces biliary damage and liver fibrosis[J]. Am J Pathol, 2020, 190(11): 2251-2266. DOI: 10.1016/j.ajpath.2020.07.007.
[30]	GLASER S, GAUDIO E, RENZI A, et al. Knockout of the neurokinin-1 receptor reduces cholangiocyte proliferation in bile duct-ligated mice[J]. Am J Physiol Gastrointest Liver Physiol, 2011, 301(2): G297-G305. DOI: 10.1152/ajpgi.00418.2010.
[31]	WAN Y, MENG F, WU N, et al. Substance P increases liver fibrosis by differential changes in senescence of cholangiocytes and hepatic stellate cells[J]. Hepatology, 2017, 66(2): 528-541. DOI: 10.1002/hep.29138.
[32]	TATEMOTO K, HOSOYA M, HABATA Y, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor[J]. Biochem Biophys Res Commun, 1998, 251(2): 471-476. DOI: 10.1006/bbrc.1998.9489.
[33]	HOSOYA M, KAWAMATA Y, FUKUSUMI S, et al. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin[J]. J Biol Chem, 2000, 275(28): 21061-21067. DOI: 10.1074/jbc.M908417199.
[34]	MELGAR-LESMES P, PERRAMON M, JIMÉNEZ W. Roles of the hepatic endocannabinoid and apelin systems in the pathogenesis of liver fibrosis[J]. Cells, 2019, 8(11): 1311. DOI: 10.3390/cells8111311.
[35]	PRINCIPE A, MELGAR-LESMES P, FERNÁNDEZ-VARO G, et al. The hepatic apelin system: A new therapeutic target for liver disease[J]. Hepatology, 2008, 48(4): 1193-1201. DOI: 10.1002/hep.22467.
[36]	REICHENBACH V, ROS J, FERNÁNDEZ-VARO G, et al. Prevention of fibrosis progression in CCl₄-treated rats: Role of the hepatic endocannabinoid and apelin systems[J]. J Pharmacol Exp Ther, 2012, 340(3): 629-637. DOI: 10.1124/jpet.111.188078.
[37]	CHEN L, ZHOU T, WHITE T, et al. The apelin-apelin receptor axis triggers cholangiocyte proliferation and liver fibrosis during mouse models of cholestasis[J]. Hepatology, 2021, 73(6): 2411-2428. DOI: 10.1002/hep.31545.