肝纤维化分子机制及治疗靶点研究进展

doi:10.3969/j.issn.1674-490X.2020.02.004

摘要/Abstract

摘要： 肝纤维化是由多种病因引起的慢性肝损伤所导致的复杂的纤维化及炎症反应发生的动态过程,可进一步进展至肝硬化及肝癌,是影响慢性肝损伤患者生命健康的一个主要问题。综述了肝纤维化发生发展过程相关的分子机制及现阶段治疗靶点的研究进展,旨在为肝纤维化的临床治疗提供依据。

关键词: 肝纤维化, 分子机制, 治疗靶点

Abstract: Liver fibrosis is a dynamic process of complex fibrosis and inflammatory reactions caused by chronic liver injury caused by multiple causes. It can further progress to cirrhosis and liver cancer, and is a major factor affecting the life and health of patients with chronic liver injury problem. This article reviews the molecular mechanisms related to the occurrence and development of liver fibrosis and the research progress of current treatment targets in order to provide a basis for the clinical treatment of liver fibrosis.

Key words: liver fibrosis, molecular mechanism, therapeutic target

中图分类号:

R575.2

闪雪纯,傅继华. 肝纤维化分子机制及治疗靶点研究进展[J]. 医学研究与教育, 2020, 37(2): 24-30.

参考文献

[1] DOOLEY S, TEN DIJKE P. TGF-β in progression of liver disease[J]. Cell Tissue Res, 2012, 347(1): 245-256. DOI: 10.1007/s00441-011-1246-y.
[2] HENDERSON N C, ARNOLD T D, KATAMURA Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs[J]. Nat Med, 2013, 19(12): 1617-1624. DOI: 10.1038/nm.3282.
[3] DING N, YU R T, SUBRAMANIAM N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response[J].Cell, 2013, 153(3): 601-613. DOI: 10.1016/j.cell.2013.03.028.
[4] YANG L, KWON J, POPOV Y, et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice[J]. Gastroenterology, 2014, 146(5): 1339-1350. DOI: 10.1053/j.gastro.2014.01.061.
[5] JEONG W I, DO S H, JEONG D H, et al. Kinetics of MMP-1 and MMP-3 produced by mast cells and macrophages in liver fibrogenesis of rat[J]. Anticancer Res, 2006, 26(5A): 3517-3526.
[6] MENG F L, WANG K, AOYAMA T. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice[J]. Gastroenterology, 2012, 143(3):765-766. DOI: 10.1053/j.gastro.2012.05.049.
[7] COBLEIGH M A, ROBEK M D. Protective and pathological properties of IL-22 in liver disease[J]. Am J Pathol, 2013, 182(1): 21-28. DOI: 10.1016/j.ajpath.2012.08.043.
[8] KRONENBERGER B, RUDLOFF I, BACHMANN M, et al. Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study[J]. BMC Med, 2012, 10: 102. DOI: 10.1186/1741-7015-10-102.
[9] MCHEDLIDZE T, WALDNER M, ZOPF S, et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis[J]. Immunity, 2013, 39(2): 357-371. DOI: 10.1016/j.immuni.2013.07.018.
[10] SCHNABL B, BRENNER D A. Interactions between the intestinal microbiome and liver diseases[J]. Gastroenterology, 2014, 146(6): 1513-1524. DOI: 10.1053/j.gastro.2014.01.020.
[11] SEKI E, SCHWABE R F. Hepatic inflammation and fibrosis: functional links and key pathways[J]. Hepatology, 2015, 61(3): 1066-1079. DOI: 10.1002/hep.27332.
[12] SEKI E, DE MINICIS S, ÖSTERREICHER C H, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis[J]. Nat Med, 2007, 13(11): 1324-1332. DOI: 10.1038/nm1663.
[13] RODERBURG C, URBAN G W, BETTERMANN K, et al. Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis[J]. Hepatology, 2011, 53(1): 209-218. DOI: 10.1002/hep.23922.
[14] FOUTS D E, TORRALBA M, NELSON K E, et al. Bacterial translocation and changes in the intestinal microbiome in mouse models of liver disease[J]. J Hepatol, 2012, 56(6): 1283-1292. DOI: 10.1016/j.jhep.2012.01.019.
[15] DE MINICIS S, RYCHLICKI C, AGOSTINELLI L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice[J]. Hepatology, 2014, 59(5): 1738-1749. DOI: 10.1002/hep.26695.
[16] DAPITO D H, MENCIN A, GWAK G Y, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4[J]. Cancer Cell, 2012, 21(4): 504-516. DOI: 10.1016/j.ccr.2012.02.007.
[17] MAZAGOVA M, WANG L R, ANFORA A T, et al. Commensal microbiota is hepatoprotective and prevents liver fibrosis in mice[J]. FASEB J, 2015, 29(3): 1043-1055. DOI: 10.1096/fj.14-259515.
[18] MEADOWS V, KENNEDY L, HARGROVE L, et al. Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2^-/- mice[J]. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(12): 165557. DOI: 10.1016/j.bbadis.2019.165557.
[19] HUANG Y H, CHEN M H, GUO Q L, et al. Interleukin-10 promotes primary rat hepatic stellate cell senescence by upregulating the expression levels of p53 and p21[J]. Mol Med Report, 2018, 17(4): 5700-5707. DOI: 10.3892/mmr.2018.8592.
[20] LUJAMBIO A, AKKARI L, SIMON J, et al. Non-cell-autonomous tumor suppression by p53[J]. Cell, 2013, 153(2): 449-460. DOI: 10.1016/j.cell.2013.03.020.
[21] HERNÁNDEZ-GEA V, GHIASSI-NEJAD Z, ROZENFELD R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues[J]. Gastroenterology, 2012, 142(4): 938-946. DOI: 10.1053/j.gastro.2011.12.044.
[22] KAUSHAL S, ANNAMALI M, BLOMENKAMP K, et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model[J]. Exp Biol Med(Maywood), 2010, 235(6): 700-709. DOI: 10.1258/ebm.2010.009297.
[23] HIDVEGI T, EWING M, HALE P, et al. An autophagy-enhancing drug promotes degradation of mutant 1-antitrypsin Z and reduces hepatic fibrosis[J]. Science, 2010, 329(5988): 229-232. DOI: 10.1126/science.1190354.
[24] SCHUPPAN D, SURABATTULA R, WANG X Y. Determinants of fibrosis progression and regression in NASH[J]. J Hepatol, 2018, 68(2): 238-250. DOI: 10.1016/j.jhep.2017.11.012.
[25] MARCELLI P, GANE E, BUTI M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study[J]. Lancet, 2013, 381(9865):468-475. DOI: 10.1016/S0140-6736(12)61425-1.
[26] LI D K, CHUNG R T. Impact of hepatitis C virus eradication on hepatocellular carcinogenesis[J]. Cancer, 2015, 121(17): 2874-2882. DOI: 10.1002/cncr.29528.
[27] PAPATHEODORIDIS G V, CHAN H L, HANSEN B E, et al. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy[J]. J Hepatol, 2015, 62(4): 956-967. DOI: 10.1016/j.jhep.2015.01.002.
[28] KARSDAL M A, MANON-JENSEN T, GENOVESE F, et al. Novel insights into the function and dynamics of extracellular matrix in liver fibrosis[J]. Am J Physiol-Gastrointest Liver Physiol, 2015, 308(10): G807-G830. DOI: 10.1152/ajpgi.00447.2014.
[29] KARSDAL M A, NIELSEN S H, LEEMING D J, et al. The good and the bad collagens of fibrosis-their role in signaling and organ function[J]. Adv Drug Deliv Rev, 2017, 121: 43-56. DOI: 10.1016/j.addr.2017.07.014.
[30] JIMÉNEZ CALVENTE C, SEHGAL A, POPOV Y, et al. Specific hepatic delivery of procollagen α1(I)small interfering RNA in lipid-like nanoparticles resolves liver fibrosis[J]. Hepatology, 2015, 62(4): 1285-1297. DOI: 10.1002/hep.27936.
[31] TAO R, FAN X X, YU H J, et al. MicroRNA-29b-3p prevents schistosoma japonicum-induced liver fibrosis by targeting COL1A1 and COL3A1[J]. J Cell Biochem, 2018, 119(4): 3199-3209. DOI: 10.1002/jcb.26475.
[32] SAKAMOTO N, OGAWA K, SUDA G, et al. Clinical phase 1b study results for safety, pharmacokinetics and efficacy of ND-L02-s0201, a novel targeted lipid nanoparticle delivering HSP47 SIRNA for the treatment of Japanese patients with advanced liver fibrosis[J]. J Hepatol, 2018, 68: S242. DOI: 10.1016/s0168-8278(18)30701-3.
[33] MITRA A, SATELLI A, YAN J, et al. IL-30(IL27p28)attenuates liver fibrosis through inducing NKG2D-Rae1 interaction between NKT and activated hepatic stellate cells in mice[J]. Hepatology, 2014, 60(6): 2027-2039. DOI: 10.1002/hep.27392.
[34] KIM-KANEYAMA J R, LEI X F, ARITA S, et al. Hydrogen peroxide-inducible clone 5(hic-5)as a potential therapeutic target for vascular and other disorders[J]. J Atheroscler Thromb, 2012, 19(7): 601-607. DOI: 10.5551/jat.10736.
[35] LEI X F, FU W G, KIM-KANEYAMA J R, et al. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice[J]. J Hepatol, 2016, 64(1): 110-117. DOI: 10.1016/j.jhep.2015.08.026.
[36] TOMITA K, TERATANI T, SUZUKI T, et al. Acyl-CoA: cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells[J]. J Hepatol, 2014, 61(1): 98-106. DOI: 10.1016/j.jhep.2014.03.018.
[37] XUE Y H, MICHALOPOULOS G. Tregs: a therapeutic target for the treatment of portal fibrosis[J]. Dig Dis Sci, 2015, 60(7): 1878-1880. DOI: 10.1007/s10620-015-3687-8.
[38] GLÄSSNER A, EISENHARDT M, KOKORDELIS P, et al. Impaired CD4⁺ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients[J]. J Hepatol, 2013, 59(3): 427-433. DOI: 10.1016/j.jhep.2013.04.029.
[39] PELLICORO A, RAMACHANDRAN P, IREDALE J P. Reversibility of liver fibrosis[J]. Fibrogenesis Tissue Repair, 2012, 5(S1): S26. DOI: 10.1186/1755-1536-5-s1-s26.
[40] PRADERE J P, KLUWE J, DE MINICIS S, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice[J]. Hepatology, 2013, 58(4): 1461-1473. DOI: 10.1002/hep.26429.
[41] BARNES M A, MCMULLEN M R, ROYCHOWDHURY S, et al. Macrophage migration inhibitory factor is required for recruitment of scar-associated macrophages during liver fibrosis[J]. J Leukoc Biol, 2015, 97(1): 161-169. DOI: 10.1189/jlb.3a0614-280r.
[42] EHLING J, BARTNECK M, WEI X, et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis[J]. Gut, 2014, 63(12): 1960-1971. DOI: 10.1136/gutjnl-2013-306294.
[43] WENG S Y, WANG X Y, VIJAYAN S, et al. IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal[J]. EBioMedicine, 2018, 29: 92-103. DOI: 10.1016/j.ebiom.2018.01.028.
[44] TACKE F, ZIMMERMANN H W. Macrophage heterogeneity in liver injury and fibrosis[J]. J Hepatol, 2014, 60(5): 1090-1096. DOI: 10.1016/j.jhep.2013.12.025.