氧化应激参与肝纤维化发生发展的研究进展

摘要/Abstract

摘要： 肝炎病毒、酒精、高脂饮食等多种致病因素可损伤肝脏,引发氧化应激。氧化应激产物活性氧(ROS)大量产生后作用于肝细胞、肝星状细胞(HSC)等多种细胞,引起肝细胞凋亡及细胞外基质(ECM)过度沉积。若未得到及时控制,将导致肝纤维化甚至肝硬化的发生。核因子E2相关因子-2/血红素加氧酶-1(Nrf2/HO-1)信号通路在机体抗氧化中起着举足轻重的作用,过量ROS可激活转录因子Nrf2,Nrf2与抗氧化反应元件(ARE)结合后,启动下游HO-1等抗氧化酶的表达,起到抗氧化,从而减轻肝纤维化的作用。本文就氧化应激及Nrf2/HO-1抗氧化通路在肝纤维化发生及进展中的影响作一综述,为肝纤维化、肝硬化的临床诊治提供新的可能思路。

关键词: 肝纤维化, 活性氧(ROS), 核因子E2相关因子-2(Nrf2), 血红素加氧酶-1(HO-1)

刘雅妮, 郭瑞芳, 王欢, 娄婷婷, 李燕. 氧化应激参与肝纤维化发生发展的研究进展[J]. 肝脏, 2023, 28(6): 724-727.

参考文献

[1] Zhou J, Zheng Q, Chen Z. The Nrf2 pathway in liver diseases. Front Cell Dev Biol, 2022,10:826204.
[2] Luangmonkong T, Suriguga S, Mutsaers H, et al. Targeting oxidative stress for the treatment of liver fibrosis. Rev Physiol Biochem Pharmacol, 2018,175:71-102.
[3] Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med, 2019,65:37-55.
[4] Roehlen N, Crouchet E, Baumert T F. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells, 2020,9(4).
[5] Tu W, Wang H, Li S, et al. The anti-inflammatory and anti-oxidant mechanisms of the keap1/nrf2/are signaling pathway in chronic diseases. Aging Dis, 2019,10(3):637-651.
[6] Gines P, Krag A, Abraldes J G, et al. Liver cirrhosis. Lancet, 2021,398(10308):1359-1376.
[7] Asrani S K, Devarbhavi H, Eaton J, et al. Burden of liver diseases in the world. J Hepatol, 2019,70(1):151-171.
[8] 吕艳杭, 吴姗姗, 王振常, 等. 中医药通过Nrf2/ARE发挥抗肝纤维化作用的研究进展. 中华中医药学刊, 2021,39(01):142-145.
[9] Sies H, Berndt C, Jones D P. Oxidative stress. Annu Rev Biochem, 2017,86:715-748.
[10] Bataller R, Brenner D A. Liver fibrosis. J Clin Invest, 2005,115(2):209-218.
[11] Liang S, Kisseleva T, Brenner D A. The role of NADPH oxidases (NOXs) in liver fibrosis and the activation of myofibroblasts. Front Physiol, 2016,7:17.
[12] Chen Z, Ma X, Zhu Y, et al. Paeoniflorin ameliorates ANIT-induced cholestasis by activating Nrf2 through an PI3K/Akt-dependent pathway in rats. Phytother Res, 2015,29(11):1768-1775.
[13] Sandalio LM, Rodriguez-Serrano M, Romero-Puertas MC, et al. Role of peroxisomes as a source of reactive oxygen species (ROS) signaling molecules. Subcell Biochem, 2013,69:231-255.
[14] Dawood RM, El-Meguid MA, Salum GM, et al. Key players of hepatic fibrosis. J Interferon Cytokine Res, 2020,40(10):472-489.
[15] Dixon LJ, Barnes M, Tang H, et al. Kupffer cells in the liver. Compr Physiol, 2013,3(2):785-797.
[16] Paik YH, Iwaisako K, Seki E, et al. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology, 2011,53(5):1730-1741.
[17] Dong S, Chen QL, Song YN, et al. Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. J Toxicol Sci, 2016,41(4):561-572.
[18] Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol, 2017,14(7):397-411.
[19] Khadrawy SM, Mohamed HM, Mahmoud AM. Mesenchymal stem cells ameliorate oxidative stress, inflammation, and hepatic fibrosis via Nrf2/HO-1 signaling pathway in rats. Environ Sci Pollut Res Int, 2021,28(2):2019-2030.
[20] Kitamura H, Motohashi H. NRF2 addiction in cancer cells. Cancer Sci, 2018,109(4):900-911.
[21] Bellezza I, Giambanco I, Minelli A, et al. Nrf2-Keap1 signaling in oxidative and reductive stress. Biochim Biophys Acta Mol Cell Res, 2018,1865(5):721-733.
[22] 张晓倩, 杨慧, 张晓华. Nrf2/HO-1信号通路在慢性肝病中的研究. 中国肝脏病杂志(电子版), 2017,9(03):36-39.
[23] Xiang M, Namani A, Wu S, et al. Nrf2: bane or blessing in cancer?. J Cancer Res Clin Oncol, 2014,140(8):1251-1259.
[24] Cullinan SB, Gordan JD, Jin J, et al. The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Mol Cell Biol, 2004,24(19):8477-8486.
[25] 张志群, 陈宏辉. 核转录因子Nrf2与肝脏疾病的研究进展. 中国现代医药杂志, 2014,16(09):99-102.
[26] Hu C, Eggler AL, Mesecar AD, et al. Modification of keap1 cysteine residues by sulforaphane. Chem Res Toxicol, 2011,24(4):515-521.
[27] Velichkova M, Hasson T. Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Mol Cell Biol, 2005,25(11):4501-4513.
[28] Saito R, Suzuki T, Hiramoto K, et al. Characterizations of three major cysteine sensors of keap1 in stress response. Mol Cell Biol, 2016,36(2):271-284.
[29] Hayes JD, Dinkova-Kostova AT. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci, 2014,39(4):199-218.
[30] Liu B, Fang M, He Z, et al. Hepatitis B virus stimulates G6PD expression through HBx-mediated Nrf2 activation. Cell Death Dis, 2015,6(11):e1980.
[31] Tang W, Jiang Y F, Ponnusamy M, et al. Role of Nrf2 in chronic liver disease. World J Gastroenterol, 2014,20(36):13079-13087.
[32] Liao W, Yang W, Shen Z, et al. Heme oxygenase-1 regulates ferrous iron and foxo1 in control of hepatic gluconeogenesis. Diabetes, 2021,70(3):696-709.
[33] Fathi R, Nasiri K, Akbari A, et al. Exercise protects against ethanol-induced damage in rat heart and liver through the inhibition of apoptosis and activation of Nrf2/Keap-1/HO-1 pathway. Life Sci, 2020,256:117958.
[34] Babusikova E, Jesenak M, Durdik P, et al. Exhaled carbon monoxide as a new marker of respiratory diseases in children. J Physiol Pharmacol, 2008,59 Suppl 6:9-17.
[35] Loboda A, Damulewicz M, Pyza E, et al. Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cell Mol Life Sci, 2016,73(17):3221-3247.
[36] 王甜甜, 陈淳媛, 杨雷, 等. Nrf2/HO-1信号轴在氧化应激性疾病中的机制. 中南大学学报(医学版), 2019,44(01):74-80.
[37] Wu TH, Wang PW, Lin TY, et al. Antioxidant properties of red raspberry extract alleviate hepatic fibrosis via inducing apoptosis and transdifferentiation of activated hepatic stellate cells. Biomed Pharmacother, 2021,144:112284.
[38] Krajka-Kuzniak V, Paluszczak J, Celewicz L, et al. Phloretamide, an apple phenolic compound, activates the Nrf2/ARE pathway in human hepatocytes. Food Chem Toxicol, 2013,51:202-209.
[39] Qiu M, Xiao F, Wang T, et al. Protective effect of Hedansanqi Tiaozhi Tang against non-alcoholic fatty liver disease in vitro and in vivo through activating Nrf2/HO-1 antioxidant signaling pathway. Phytomedicine, 2020,67:153140.
[40] Zhao Z, Wang C, Zhang L, et al. Lactobacillus plantarum NA136 improves the non-alcoholic fatty liver disease by modulating the AMPK/Nrf2 pathway. Appl Microbiol Biotechnol, 2019,103(14):5843-5850.