原发性胆汁性胆管炎的药物治疗新靶点

陈荣彬; 吴学铭; 吴颖; 姚定康

doi:10.3969/j.issn.1001-5256.2017.05.044

原发性胆汁性胆管炎的药物治疗新靶点

DOI: 10.3969/j.issn.1001-5256.2017.05.044

第二军医大学第二附属医院

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中图分类号: R575.7
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出版历程
- 出版日期: 2017-05-20

Novel therapeutic targets for primary biliary cholangitis

The Second Affiliated Hospital of Second Military Medical University

摘要

摘要: 原发性胆汁性胆管炎以进展性胆汁淤积,肝内中小胆管非化脓性炎症为表现,最终发展成肝硬化、肝癌,严重威胁患者生命。研究发现熊去氧胆酸可有效治疗原发性胆汁性胆管炎。对熊去氧胆酸反应较差的患者接受移植或死亡的比例逐年增加,亟需新治疗方案。新药物作用于疾病进展的关键进程,如"上游"免疫反应,"中游"胆道损伤和"下游"纤维化进程。针对不同通路的多药物联合治疗是未来的发展趋势。总结了目前原发性胆汁性胆管炎的潜在治疗方案,评估了治疗实施所面临的挑战。
- 肝硬化,胆汁性 /
- 治疗 /
- 综述
Abstract: Primary biliary cholangitis (PBC) is a chronic autoimmune-mediated liver disease manifesting as progressive cholestasis and non-purulent inflammation in small-and medium-sized intrahepatic bile ducts.It finally progresses to liver cirrhosis and liver cancer and greatly threatens patient's life.Studies have found that ursodeoxycholic acid (UDCA) can treat PBC effectively.There is a constant increase in the proportion of patients with poor response to UDCA who have undergone transplantation or died, and therefore, new therapeutic regimens should be developed as soon as possible.It is necessary to develop new drugs which act on the key processes of disease progression, such as the "upstream" immune response, the "midstream" bile duct injury, and the "downstream" fibrotic process.Combination treatment with drugs targeting different pathways is a trend for future development.This article summarizes current potential therapeutic regimens for PBC and assesses the challenges in the treatment of PBC.
- liver cirrhosis, biliary /
- therapy /
- review

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参考文献(40)

[1]BEUERS U, GERSHWIN ME, GISH RG, et al.Changing nomenclature for PBC:from‘cirrhosis’to‘cholangitis’[J].Gut, 2015, 64 (11) :1671-1672.

[2]CARBONE M, MELLS GF, PELLS G, et al.Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid[J].Gastorenterology, 2013, 144 (3) :560-569.

[3]MELLS GF, FLOYD JA, MORLEY KI, et al.Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis[J].Nat Genet, 2011, 43 (4) :329-332.

[4]HIRSCHFIELD GM, GERSHWIN ME, STRAUSS R, et al.Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid:a proof-of-concept study[J].Hepatology, 2016, 64 (1) :189-199.

[5]AFFORD SC, AHMED-CHOUDHURY J, RANDHAWA S, et al.CD40 activation-induced, Fas-dependent apoptosis and NF-kappa B/AP-1 signaling in human intrahepatic biliary epithelial cells[J].FASEB J, 2001, 15 (13) :2345-2354.

[6]MYERS RP, SWAIN MG, LEE SS, et al.B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid[J].Am J Gastroenterol, 2013, 108 (6) :933-941.

[7]LENS S, LEOZ M, NAZAL L, et al.Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid[J].Liver Int, 2014, 34 (2) :197-203.

[8]NEVENS F, ANDREONE P, MAZZELLA G, et al.A placebocontrolled trial of obeticholic acid in primary billary cholangitis[J].N Engl J Med, 2016, 375 (7) :631-643.

[9]LIASKOU E, HIRSCHFIELD GM, GERSHWIN ME, et al.Mechanisms of tissue injury in autoimmune liver diseases[J].Semin Immunopathol, 2014, 36 (5) :553-568.

[10]KITA H, LIAN ZX, van de WATER J, et al.Identification of HLA-A2-restricted CD8+cytotoxic T-cell responses in primary biliary cirrhosis:T-cell activation is augmented by immune complexes cross presented by dendritic cells[J].J Exp Med, 2002, 195 (1) :113-123.

[11]MAILLETTE de BUY WENNIGER LJ, OUDE ELFERINK RP, BEUERS U.Molecular targets for the treatment of fibrosing cholangiopathies[J].Clin Pharmacol Ther, 2012, 92 (3) :381-387.

[12]BEUERS U, NATHANSON MH, ISALES CM, et al.Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++mechanisms defective in cholestasis[J].J Clin Invest, 1993, 92 (6) :2984-2993.

[13]BEUERS U.β1-Integrin is a long-sought sensor for tauroursodeoxycholic acid[J].Hepatology, 2013, 57 (3) :867-869.

[14]HOHENESTER S, WENNIGER LM, PAULUSMA CC, et al.Abiliary HCO-3umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes[J].Hepatology, 2012, 55 (1) :173-183.

[15]BAGHDASARYAN A, CLAUDEL T, GUMHOLD J, et al.Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/- (Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO3-output[J].Hepatology, 2011, 54 (4) :1303-1312.

[16]GHONEM NS, ANANTHANARAYANAN M, SOROKA CJ, et al.Peroxisome proliferator-activated receptor alpha activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion[J].Hepatology, 2014, 59 (3) :1030-1042.

[17]BYUN HO, LEE YK, KIM JM, et al.From cell senescence to age-related diseases:differential mechanisms of action of senescence-associated secretory phenotypes[J].BMB Rep, 2015, 48 (10) :549-558.

[18]WANG Q, DAI X, YANG W, et al.Caffeine protects against alcohol-induced liver fibrosis by dampening the c AMP/PKA/CREBpathway in rat hepatic stellate cells[J].Int Immunopharmacol, 2015, 25 (2) :340-352.

[19]LIU Z, YI J, YE R, et al.miR-144 regulates transforming growth factor-β1 iduced hepatic stellate cell activation in human fibrotic liver[J].Int J Clin Exp Pathol, 2015, 8 (4) :3994-4000.

[20]IWAISAKO K, JIANG C, ZHANG M, et al.Origin of myofibroblasts in the fibrotic liver in mice[J].Proc Natl Acad Sci USA, 2014, 111 (32) :e3297-e3305.

[21]POPOV Y, PATSENKER E, FICKERT P, et al.Mdr2 (Abcb4) -/-mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro-and antifibrogenic genes[J].J Hepatol, 2005, 43 (6) :1045-1054.

[22]POPOV Y, PATSENKER E, STICKEL F, et al.Integrinαvβ6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies[J].J Hepatol, 2008, 48 (3) :453-464.

[23]PENG ZW, IKENAGA N, LIU SB, et al.Integrinαvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis[J].Hepatology, 2016, 63 (1) :217-232.

[24]POUPON R.Ursodeoxycholic acid and bile-acid mimetics as therapeutic agents for cholestatic liver diseases:an overview of their mechanisms of action[J].Clin Res Hepatol Gastroenterol, 2012, 36 (Suppl 1) :s3-s12.

[25]SOMBETZKI M, FUCHS CD, FICKERT P, et al.24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosis in a murine model of hepatic schistosomiasis[J].J Hepatol, 2015, 62 (4) :871-878.

[26]NEVENS F, ANDREONE P, MAZZELLA G, et al.The first primary biliary cirrhosis (PBC) phase 3 trial in two decades-an international study of the FXR agonist obeticholic acid in PBC patients[J].J Hepatol, 2014, 60 (1) :s525-s526.

[27]HIRSCHFIELD GM, MASON A, LUKETIC V, et al.Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid[J].Gastroenterology, 2015, 148 (4) :751-761.

[28]BEUERS U, KREMER AE, BOLIER R, et al.Pruritus in cholestasis:facts and fiction[J].Hepatology, 2014, 60 (1) :399-407.

[29]LECKIE P, TRITTO G, MOOKERJEE R, et al.'Out-patient'albumin dialysis for cholestatic patients with intractable pruritus[J].Aliment Pharmacol Ther, 2012, 35 (6) :696-704.

[30]KREMER AE, NAMER B, BOLIER R, et al.Pathogenesis and management of pruritus in PBC and PSC[J].Dig Dis, 2015, 33 (Suppl 2) :164-175.

[31]US National Library of Medicine.Clinical Trials.gov[EB/OL].2014, https://clinicaltrials.gov/ct2/show/NCT01904058.

[32]US National Library of Medicine.Clinical Trials.gov[EB/OL].2014, https://clinicaltrials.gov/ct2/show/NCT01899703.

[33]KREMER AE, DIJK R, LECKIE P, et al.Serum autotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions[J].Hepatology, 2012, 56 (4) :1391-1400.

[34]ALEMI F, KWON E, POOLE DP, et al.The TGR5 receptor mediated bile acid-induce itch and analgesia[J].J Clin Invest, 2013, 123 (4) :1513-1530.

[35]KEITEL V, REICH M, HAUSSINGER D, et al.TGR5:pathogenetic role and/or therapeutic target in fibrosing cholangitis?[J].Clin Rev Allergy Immunol, 2015, 48 (2-3) :218-225.

[36]JOPSON L, JONES DE.Fatigue in primary biliary cirrhosis:prevalence, pathogenesis and management[J].Dig Dis, 2015, 33 (Suppl 2) :109-114.

[37]D'MELLO C, RIAZI K, LE T, et al.P-selectin-mediated monocyte-cerebral endothelium adhesive interactions link peripheral organ inflammation to sickness behaviors[J].J Neurosci, 2013, 33 (37) :14878-14888.

[38]HOLLINGSWORTH KG, JONES DE, TAYLOR R, et al.Impaired cerebral autoregulation in primary biliary cirrhosis:implications for the pathogenesis of cognitive decline[J].Liver Int, 2010, 30 (6) :878-885.

[39]DIONISIO PA, AMARAL JD, RIBEIRO MF, et al.Amyloid-βpathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset[J].Neurobiol Aging, 2015, 36 (1) :228-240.

[40]HOLLINGSWORTH KG, NEWTON JL, TAYLOR R, et al.Pilot study of peripheral muscle function in primary biliary cirrhosis:potential implications for fatigue pathogenesis[J].Clin Gastroenterol Hepatol, 2008, 6 (9) :1041-1048.

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