肝纤维化发生及逆转途径的研究进展

doi:10.3969/j.issn.1004-616x.2022.03.013

摘要/Abstract

摘要： 肝纤维化是慢性或持续性肝损伤的最终共同途径,晚期常会进展为肝硬化和肝癌而危及生命。来自动物模型和临床的证据表明,当病原体被去除时,肝纤维化会消退,这与激活的肌成纤维细胞的消除和纤维瘢痕的吸收有关,所以了解肝纤维化消退的机制可以帮助确定治疗新的肝纤维化治疗靶点。本文主要讲述了肝纤维化的损伤机制,以及在应对肝纤维化的可逆性上,从细胞外基质的平衡,肝星状细胞的凋亡和失活、各种免疫细胞以及不同细胞信号通路,自噬等方面简要介绍如何协调和解决肝纤维化,以期为肝纤维化相关疾病的治疗和进一步研究提供理论指导。

关键词: 肝纤维化, 病理机制, 肝星状细胞, 细胞外基质, 免疫细胞

中图分类号:

R575.2

苏静, 胡以平. 肝纤维化发生及逆转途径的研究进展[J]. 癌变·畸变·突变, 2022, 34(3): 242-246.

SU Jing, HU Yiping. [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(3): 242-246.

参考文献

[1] ASRANI S K, DEVARBHAVI H, EATON J, et al. Burden of liver diseases in the world[J]. J Hepatol, 2019, 70(1):151-171.
[2] SEKI E, SCHWABE R F. Hepatic inflammation and fibrosis:functional links and key pathways[J]. Hepatology, 2015, 61(3):1066-1079.
[3] AYD\U0131N M M, AKÇAL\U0131 K C. Liver fibrosis[J]. Turk J Gastroenterol, 2018, 29(1):14-21.
[4] KISSELEVA T, BRENNER D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021,18(3):151-166.
[5] SEKI E, SCHWABE R F. Hepatic inflammation and fibrosis:functional links and key pathways[J]. Hepatology, 2015, 61(3):1066-1079.
[6] CAMPANA L, IREDALE J P. Regression of liver fibrosis[J]. Semin Liver Dis, 2017, 37(1):1-10.
[7] ELLIS E L, MANN D A. Clinical evidence for the regression of liver fibrosis[J]. J Hepatol, 2012, 56(5):1171-1180.
[8] ISSA R, ZHOU X Y, CONSTANDINOU C M, et al. Spontaneous recovery from micronodular cirrhosis:evidence for incomplete resolution associated with matrix cross-linking[J]. Gastroenterology, 2004, 126(7):1795-1808.
[9] POYNARD T, MCHUTCHISON J, MANNS M, et al. Impact of pegylated interferon Alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C[J]. Gastroenterology, 2002, 122(5):1303-1313.
[10] HIGASHI T, FRIEDMAN S L, HOSHIDA Y. Hepatic stellate cells as key target in liver fibrosis[J]. Adv Drug Deliv Rev, 2017, 121:27-42.
[11] MARTÍ-RODRIGO A, ALEGRE F, MORAGREGAÁB, et al.Rilpivirine attenuates liver fibrosis through selective STAT1-mediated apoptosis in hepatic stellate cells[J]. Gut, 2020, 69(5):920-932.
[12] LUEDDE T, SCHWABE R F. NF-κB in the liver:linking injury,fibrosis and hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 8(2):108-118.
[13] BORKHAM-KAMPHORST E, SCHAFFRATH C, VAN DE LEUR E,et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-β signaling[J]. Biochim Biophys Acta, 2014, 1843(5):902-914.
[14] MÒDOL T, BRICE N, RUIZ DE GALARRETA M, et al. Fibronectin peptides as potential regulators of hepatic fibrosis through apoptosis of hepatic stellate cells[J]. J Cell Physiol, 2015, 230(3):546-553.
[15] KOU X Y, SUN Y Y, LI S J, et al. Pharmacology study of the multiple angiogenesis inhibitor RC28-E on anti-fibrosis in a chemically induced lung injury model[J]. Biomolecules, 2019, 9(11):644.
[16] WANG C, LI Y L, LI H, et al. Disruption of FGF signaling ameliorates inflammatory response in hepatic stellate cells[J]. Front Cell Dev Biol,2020, 8:601.
[17] TAO L, MA W T, WU L, et al. Glial cell line-derived neurotrophic factor(GDNF)mediates hepatic stellate cell activation via ALK5/Smad signalling[J]. Gut, 2019, 68(12):2214-2227.
[18] ZHANG Q H, XIANG S H, LIU Q Q, et al. PPAR γ antagonizes hypoxia-induced activation of hepatic stellate cell through cross mediating PI3K/AKT and cGMP/PKG signaling[J]. PPAR Res, 2018,2018:6970407.
[19] STEFANOVIC B, MANOJLOVIC Z, VIED C, et al. Discovery and evaluation of inhibitor of LARP6 as specific antifibrotic compound[J].Sci Rep, 2019, 9(1):326.
[20] ZUO S K, WANG B, LIU J, et al. ER-anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6[J]. EMBO J,2021, 40(16):e107403.
[21] FAN W G, LIU T H, CHEN W, et al. ECM1 prevents activation of transforming growth factor β, hepatic stellate cells, and fibrogenesis in mice[J]. Gastroenterology, 2019, 157(5):1352-1367.
[22] SUN W Y, GU Y J, LI X R, et al.Β-arrestin2 deficiency protects against hepatic fibrosis in mice and prevents synthesis of extracellular matrix[J]. Cell Death Dis, 2020, 11(5):389.
[23] IIMURO Y, NISHIO T, MORIMOTO T, et al. Delivery of matrix metalloproteinase-1 attenuates established liver fibrosis in the rat[J].Gastroenterology, 2003, 124(2):445-458.
[24] GARCIA-BAÑUELOS J, SILLER-LOPEZ F, MIRANDA A, et al.Cirrhotic rat livers with extensive fibrosis can be safely transduced with clinical-grade adenoviral vectors. Evidence of cirrhosis reversion[J].Gene Ther, 2002, 9(2):127-134.
[25] RODERFELD M, WEISKIRCHEN R, WAGNER S, et al. Inhibition of hepatic fibrogenesis by matrix metalloproteinase-9 mutants in mice[J].FASEB J, 2006, 20(3):444-454.
[26] TSAY H C, YUAN Q G, BALAKRISHNAN A, et al. Hepatocytespecific suppression of microRNA-221-3p mitigates liver fibrosis[J]. J Hepatol, 2019, 70(4):722-734.
[27] KLEPFISH M, GROSS T, VUGMAN M, et al. LOXL2 inhibition paves the way for macrophage-mediated collagen degradation in liver fibrosis[J]. Front Immunol, 2020, 11:480.
[28] CHEN G B, XIA B, FU Q, et al. Matrix mechanics as regulatory factors and therapeutic targets in hepatic fibrosis[J]. Int J Biol Sci, 2019, 15(12):2509-2521.
[29] MOSSANEN J C, KRENKEL O, CAN E G, et al. Chemokine(C-C motif)receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury[J]. Hepatology, 2016, 64(5):1667-1682.
[30] FRIEDMAN S L, RATZIU V, HARRISON S A, et al. A randomized,placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis[J]. Hepatology, 2018, 67(5):1754-1767.
[31] YOUNOSSI Z M, STEPANOVA M, LAWITZ E, et al. Improvement of hepatic fibrosis and patient-reported outcomes in non-alcoholic steatohepatitis treated with selonsertib[J]. Liver Int, 2018, 38(10):1849-1859.
[32] RATZIU V, SANYAL A, HARRISON S A, et al. Cenicriviroc treatment for adults with nonalcoholic steatohepatitis and fibrosis:final analysis of the phase 2b CENTAUR study[J]. Hepatology, 2020, 72(3):892-905.
[33] BOULTER L, GOVAERE O, BIRD T G, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease[J]. Nat Med, 2012, 18(4):572-579.
[34] DUFFIELD J S, FORBES S J, CONSTANDINOU C M, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair[J]. J Clin Invest, 2005, 115(1):56-65.
[35] CHANG J, HISAMATSU T, SHIMAMURA K, et al. Activated hepatic stellate cells mediate the differentiation of macrophages[J]. Hepatol Res,2013, 43(6):658-669.
[36] MATSUDA M, SEKI E. The liver fibrosis niche:novel insights into the interplay between fibrosis-composing mesenchymal cells, immune cells,endothelial cells, and extracellular matrix[J]. Food Chem Toxicol, 2020,143:111556.
[37] THAPA M, CHINNADURAI R, VELAZQUEZ V M, et al. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity[J]. Hepatology, 2015, 61(6):2067-2079.
[38] WYNN T A. Fibrotic disease and the T(H)1/T(H)2paradigm[J]. Nat Rev Immunol, 2004, 4(8):583-594.
[39] ZHANG M J, ZHANG S. T cells in fibrosis and fibrotic diseases[J].Front Immunol, 2020, 11:1142.
[40] LIU Y, LU T F, ZHANG C, et al. Activation of YAP attenuates hepatic damage and fibrosis in liver ischemia-reperfusion injury[J]. J Hepatol,2019, 71(4):719-730.
[41] MOORING M, FOWL B H, LUM S Z C, et al. Hepatocyte stress increases expression of yes-associated protein and transcriptional coactivator with PDZ-binding motif in hepatocytes to promote parenchymal inflammation and fibrosis[J]. Hepatology, 2020, 71(5):1813-1830.
[42] RONG X L, YANG Y Y, ZHANG G K, et al. Antler stem cells as a novel stem cell source for reducing liver fibrosis[J]. Cell Tissue Res,2020, 379(1):195-206.
[43] LAN L, LIU R, QIN L Y, et al. Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis[J]. World J Gastroenterol, 2018, 24(2):237-247.
[44] WAN J H, WEISS E, BEN MKADDEM S, et al. LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling[J]. Sci Transl Med, 2020, 12(539):eaaw8523.
[45] HERNÁNDEZ-GEA V, HILSCHER M, ROZENFELD R, et al.Endoplasmic Reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy[J]. J Hepatol, 2013, 59(1):98-104.