碳酸氢根伞在原发性胆汁性胆管炎发病机制中的作用
DOI: 10.3969/j.issn.1001-5256.2021.03.043
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:常英昊负责收集分析文献与论文撰写,同时参与拟定了写作思路;景丹、徐文姣参与了收集分析文献以及论文修改;周晓蕾、王孝平参与了收集分析文献;汤善宏负责拟定写作思路,指导撰写文章与最后定稿。
Role of HCO3- umbrella in the pathogenesis of primary biliary cholangitis
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摘要: 原发性胆汁性胆管炎(PBC)是一种自身免疫性疾病。虽然PBC具有自身免疫性疾病的特征,但是免疫抑制剂对其疗效不佳,而熊去氧胆酸等参与调节胆汁酸代谢的药物却具有良好疗效。研究显示PBC患者胆管上皮细胞的碳酸氢根(HCO3-)分泌功能受损,失去HCO3-伞阻挡的胆汁酸进入胆管上皮细胞并介导细胞损伤与凋亡,引发凋亡细胞表达自身抗原并造成免疫损伤。为探究胆管上皮细胞所分泌的HCO3-伞在PBC发病机制中的作用, 简述了HCO3-伞的生理功能与产生机制,以及HCO3-分泌的影响因素等,并指出HCO3-分泌减少可能是PBC发病机制的关键环节和潜在治疗靶点。Abstract: Primary biliary cholangitis (PBC) is an autoimmune disease. Although PBC has the features of autoimmune disease, it has poor response to immunosuppressants and good response to the drugs participating in bile acid metabolism, such as ursodeoxycholic acid. Studies have shown that the bicarbonate secretion of biliary epithelial cells is impaired in PBC patients, and bile acid not blocked by HCO3- umbrella enters biliary epithelial cells and mediates their damage and apoptosis, leading to the expression of autoantibodies in apoptotic cells and immunologic injury. In order to explore the role of HCO3- umbrella secreted by biliary epithelial cells in the pathogenesis of PBC, this article briefly introduces the physiological function and production mechanism of HCO3- umbrella and the influencing factors for HCO3- secretion, and it is pointed out that reduced HCO3- secretion may be a key link in the pathogenesis of PBC and a potential therapeutic target.
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Key words:
- Liver Cirrhosis, Biliary /
- Bicarbonates /
- Bile Acids and Salts /
- Biliary Epithelial Cells
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[1] MEDINA JF. Role of the anion exchanger 2 in the pathogenesis and treatment of primary biliary cirrhosis[J]. Dig Dis, 2011, 29(1): 103-112. DOI: 10.1159/000324144 [2] SASAKI M, SATO Y, NAKANUMA Y. An impaired biliary bicarbonate umbrella may be involved in dysregulated autophagy in primary biliary cholangitis[J]. Lab Invest, 2018, 98(6): 745-754. DOI: 10.1038/s41374-018-0045-4 [3] DEUTSCHMANN K, REICH M, KLINDT C, et al. Bile acid receptors in the biliary tree: TGR5 in physiology and disease[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1319-1325. http://www.ncbi.nlm.nih.gov/pubmed/28844960 [4] BEUERS U, HOHENESTER S, MAILLETTE BW, et al. The biliary HCO3- umbrella: A unifying hypothesis on pathogenetic and therapeutic aspects of fibrosingcholangiopathies[J]. Hepatology, 2010, 52(4): 1489-1496. DOI: 10.1002/hep.23810 [5] MAILLETTE de BUY WENNIGER LJ, HOHENESTER S, MARONI L, et al. The cholangiocyte glycocalyx stabilizes the 'biliary HCO3 umbrella': An integrated line of defense against toxic bile acids[J]. Dig Dis, 2015, 33(3): 397-407. DOI: 10.1159/000371864 [6] HOHENESTER S, WENNIGER LM, PAULUSMA CC, et al. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes[J]. Hepatology, 2012, 55(1): 173-183. DOI: 10.1002/hep.24691 [7] LI M, CAI SY, BOYER JL. Mechanisms of bile acid mediated inflammation in the liver[J]. Mol Aspects Med, 2017, 56: 45-53. DOI: 10.1016/j.mam.2017.06.001 [8] THAKKAR N, SLIZGI JR, BROUWER K. Effect of liver disease on hepatic transporter expression and function[J]. J Pharm Sci, 2017, 106(9): 2282-2294. DOI: 10.1016/j.xphs.2017.04.053 [9] van NIEKERK J, KERSTEN R, BEUERS U. Role of bile acids and the biliary HCO3- umbrella in the pathogenesis of primary biliary cholangitis[J]. Clin Liver Dis, 2018, 22(3): 457-479. DOI: 10.1016/j.cld.2018.03.013 [10] BOYER JL. Bile formation and secretion[J]. Compr Physiol, 2013, 3(3): 1035-1078. [11] WU N, MENG F, ZHOU T, et al. The secretin/secretin receptor axis modulates ductular reaction and liver fibrosis through changes in transforming growth factor-β1-mediated biliary senescence[J]. Am J Pathol, 2018, 188(10): 2264-2280. DOI: 10.1016/j.ajpath.2018.06.015 [12] MINAGAWA N, NAGATA J, SHIBAO K, et al. Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile[J]. Gastroenterology, 2007, 133(5): 1592-1602. DOI: 10.1053/j.gastro.2007.08.020 [13] TIETZ PS, MARINELLI RA, CHEN XM, et al. Agonist-induced coordinated traffickingof functionally related transport proteins for water and ions in cholangiocytes[J]. J Biol Chem, 2003, 278(22): 20413-20419. DOI: 10.1074/jbc.M302108200 [14] STEEGBORN C. Structure, mechanism, and regulation of soluble adenylyl cyclases-similarities and differences to transmembrane adenylyl cyclases[J]. Biochim Biophys Acta, 2014, 1842(12 Pt B): 2535-2547. http://europepmc.org/abstract/med/25193033 [15] PRIETO J, GARCÍA N, MARTÍ-CLIMENT JM, et al. Assessment of biliary bicarbonate secretion in humans by positron emission tomography[J]. Gastroenterology, 1999, 117(1): 167-172. DOI: 10.1016/S0016-5085(99)70564-0 [16] JURAN BD, LAZARIDIS KN. Update on the genetics and genomics of PBC[J]. J Autoimmun, 2010, 35(3): 181-187. DOI: 10.1016/j.jaut.2010.06.005 [17] KOUROUMALIS E, SAMONAKIS D, VOUMVOURAKI A. Biomarkers for primary biliary cholangitis: Current perspectives[J]. Hepat Med, 2018, 10: 43-53. DOI: 10.2147/HMER.S135337 [18] ARENAS F, HERVÍAS I, SÁEZ E, et al. Promoter hypermethylation of the AE2/SLC4A2 gene in PBC[J]. JHEP Rep, 2019, 1(3): 145-153. DOI: 10.1016/j.jhepr.2019.05.006 [19] ERICE O, MUNOZ-GARRIDO P, VAQUERO J, et al. MicroRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation[J]. Hepatology, 2018, 67(4): 1420-1440. DOI: 10.1002/hep.29533 [20] MEENAKSHISUNDARAM A, JESUS MB, MATEUS TG, et al. Post-translational regulation of the type Ⅲ inositol 1, 4, 5-trisphosphate receptor by miRNA-506[J]. J BiolChem, 2015, 290(1): 184-196. http://www.sciencedirect.com/science/article/pii/S0021925820579192 [21] KLEINBOELTING S, DIAZ A, MONIOT S, et al. Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate[J]. Proc Natl Acad Sci U S A, 2014, 111(10): 3727-3732. DOI: 10.1073/pnas.1322778111 [22] CHANG JC, GO S, de WAART DR, et al. Soluble adenylyl cyclase regulates bile salt-induced apoptosis in human cholangiocytes[J]. Hepatology, 2016, 64(2): 522-534. DOI: 10.1002/hep.28550 [23] CHANG JC, GO S, VERHOEVEN AJ, et al. Role of the bicarbonate-responsive soluble adenylyl cyclase in cholangiocyte apoptosis in primary biliary cholangitis; A new hypothesis[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(4 Pt B): 1232-1239. http://europepmc.org/abstract/MED/28962898 [24] FUKUI H. Increased intestinal permeability and decreased barrier function: Does it really influence the risk of inflammation?[J]. Inflamm Intest Dis, 2016, 1(3): 135-145. DOI: 10.1159/000447252 [25] KIZILTAS S. Toll-like receptors in pathophysiology of liver diseases[J]. World J Hepatol, 2016, 8(32): 1354-1369. DOI: 10.4254/wjh.v8.i32.1354 [26] ZHU M, AN Y, ZHANG X, et al. Experimental pulmonary fibrosis was suppressed by microRNA-506 through NF-kappa-mediated apoptosis and inflammation[J]. Cell Tissue Res, 2019, 378(2): 255-265. DOI: 10.1007/s00441-019-03054-2 [27] FRANCA A, CARLOS MELO LIMA FILHO A, GUERRA MT, et al. Effects of endotoxin on type 3 inositol 1, 4, 5-trisphosphate receptor in human cholangiocytes[J]. Hepatology, 2019, 69(2): 817-830. DOI: 10.1002/hep.30228 [28] TSUBOI H, OHIRA H, ASASHIMA H, et al. Anti-M3 muscarinic acetylcholine receptor antibodies in patients with primary biliary cirrhosis[J]. Hepatol Res, 2014, 44(14): e471-e479. DOI: 10.1111/hepr.12346 [29] CONCEPCION AR, LOPEZ M, ARDURA-FABREGAT A, et al. Role of AE2 for pHi regulation in biliary epithelial cells[J]. Front Physiol, 2013, 4: 413. http://www.ncbi.nlm.nih.gov/pubmed/24478713 [30] SAMANT H, MANATSATHIT W, DIES D, et al. Cholestatic liver diseases: An era of emerging therapies[J]. World J Clin Cases, 2019, 7(13): 1571-1581. DOI: 10.12998/wjcc.v7.i13.1571
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