中性粒细胞胞外诱捕网（NET）与肝脏疾病的关系

仁增卓嘎; 杨康洁; 芦永良; 王志鑫; 王海久

doi:10.12449/JCH240334

中性粒细胞胞外诱捕网（NET）与肝脏疾病的关系

DOI: 10.12449/JCH240334

仁增卓嘎^{1a, 2},
杨康洁^1b,
芦永良^1b,
王志鑫^1a,
王海久^1a, , ,

1a.
青海大学附属医院肝胆外科，西宁 810001
1b.
青海大学附属医院检验科，西宁 810001
2.
拉萨市人民医院麻醉科，拉萨 850000

基金项目:

青海省科技厅临床医学研究中心项目 (2017-SF-L2)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：仁增卓嘎负责课题设计，收集文献，撰写论文；杨康洁参与图片制作；王志鑫参与论文修改；芦永良、王海久等负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
王海久， wanghaijiuqy@126.com （ORCID： 0000-0001-6033-238X）

计量
- 文章访问数: 429
- HTML全文浏览量: 217
- PDF下载量: 53
- 被引次数: 0
出版历程
- 收稿日期: 2023-06-24
- 录用日期: 2023-07-10
- 出版日期: 2024-03-20

Research advances in neutrophil extracellular traps and liver diseases

Zhuoga RENZENG^{1a, 2},
Kangjie YANG^1b,
Yongliang LU^1b,
Zhixin WANG^1a,
Haijiu WANG^{1a
, ,
,}

1a.
Department of Hepatobiliary Surgery，The Affiliated Hospital of Qinghai University，Qinghai 810001，China
1b.
Department of Clinical Laboratory，The Affiliated Hospital of Qinghai University，Qinghai 810001，China
2.
Department of Anesthesia，Lhasa People’s Hospital，Lhasa 850000，China

Research funding:

Qinghai Provincial Department of Science and Technology Clinical Medical Research Center Project (2017-SF-L2)

More Information

Corresponding author: WANG Haijiu， wanghaijiuqy@126.com （ORCID： 0000-0001-6033-238X）

摘要

摘要: 中性粒细胞通过释放中性粒细胞弹性蛋白酶和髓过氧化物酶等蛋白酶，形成中性粒细胞胞外诱捕网（NET），在体内发挥免疫防御作用，并参与多种肝病的炎性反应，但其过度释放会加重肝组织损伤，成为肝脏疾病的危险因素之一。近年来，有研究发现NET的过度释放可促进病毒性肝炎、非酒精性脂肪性肝炎、肝脏缺血再灌注损伤等疾病向肝癌进展，阐明NET作用机制对肝脏疾病的诊断和进展过程具有重要意义。本文主要阐述NET在肝脏疾病中的最新研究进展，为肝脏疾病的诊疗和预防提供新的思路。
- 胞外诱捕网 /
- 肝疾病 /
- 肝肿瘤
Abstract: Neutrophils play an immune defense role by releasing the proteases such as neutrophil elastase and myeloperoxidase to form neutrophil extracellular trap （NET） and participate in the inflammatory response of various liver diseases， but the excessive release of NET may worsen liver tissue damage and has thus become one of the risk factors for liver diseases. In recent years， studies have shown that the excessive release of NET can promote the progression of liver diseases （such as viral hepatitis， nonalcoholic steatohepatitis， and hepatic ischemia-reperfusion injury） to liver cancer， and clarifying the mechanism of action of NET is of great importance for the diagnosis and progression of liver diseases. Therefore， this article elaborates on the latest research advances in NET in liver diseases， so as to provide new insights into the diagnosis and treatment of liver diseases and the prevention of liver cancer.
- Extracellular Traps /
- Liver Diseases /
- Liver Neoplasms

HTML全文

图 1 NET形成与肝脏病理机制

Figure 1. NET formation and hepatic pathology

下载: 全尺寸图片幻灯片

图 2 NET与肝脏疾病的联系

Figure 2. The association of NET with liver disease

下载: 全尺寸图片幻灯片

表 1 影响肝缺血再灌注损伤的因素

Table 1. Factors that influence hepatic ischemia and reperfusion injury

影响因素	机制	NET释放	参考文献
增加因素
HMGB1	刺激TLR4/TLR9	+	［17］
丙烯醛	刺激NOX2和P38 MAPK	+	［22］
IL-17A	炎症风暴的中心驱动因子	+	［18］
HRG	中性粒细胞浸润	+	［19］
抑制因素
二苯碘胺（DPI）	NADPH氧化酶抑制剂	-	［21］
苯甲酸酰肼	MPO氧化酶抑制剂	-	［21］
西维来司	NE抑制剂	-	［21］
阿司匹林、氯吡格雷	血小板活性抑制	-	［21］
羟氯喹	抑制TLR9	-	［16］
姜黄素	抑制MEK/ERK	-	［20］

下载: 导出CSV

参考文献(31)

[1]	HILSCHER MB, SHAH VH. Neutrophil extracellular traps and liver disease[J]. Semin Liver Dis, 2020, 40( 2): 171- 179. DOI: 10.1055/s-0039-3399562.
[2]	LINHARES-LACERDA L, TEMEROZO JR, RIBEIRO-ALVES M, et al. Neutrophil extracellular trap-enriched supernatants carry microRNAs able to modulate TNF-α production by macrophages[J]. Sci Rep, 2020, 10( 1): 2715. DOI: 10.1038/s41598-020-59486-2.
[3]	VARRICCHI G, MODESTINO L, POTO R, et al. Neutrophil extracellular traps and neutrophil-derived mediators as possible biomarkers in bronchial asthma[J]. Clin Exp Med, 2022, 22( 2): 285- 300. DOI: 10.1007/s10238-021-00750-8.
[4]	TABRIZI ZA, KHOSROJERDI A, ASLANI S, et al. Multi-facets of neutrophil extracellular trap in infectious diseases: Moving beyond immunity[J]. Microb Pathog, 2021, 158: 105066. DOI: 10.1016/j.micpath.2021.105066.
[5]	CHAPMAN EA, LYON M, SIMPSON D, et al. Caught in a trap? proteomic analysis of neutrophil extracellular traps in rheumatoid arthritis and systemic lupus erythematosus[J]. Front Immunol, 2019, 10: 423. DOI: 10.3389/fimmu.2019.00423.
[6]	JORCH SK, KUBES P. An emerging role for neutrophil extracellular traps in noninfectious disease[J]. Nat Med, 2017, 23( 3): 279- 287. DOI: 10.1038/nm.4294.
[7]	HELMY KY, KATSCHKE KJ Jr, GORGANI NN, et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens[J]. Cell, 2006, 124( 5): 915- 927. DOI: 10.1016/j.cell.2005.12.039.
[8]	MEIJENFELDT F, JENNE CN. Netting liver disease: neutrophil extracellular traps in the initiation and exacerbation of liver pathology[J]. Semin Thromb Hemost, 2020, 46( 6): 724- 734. DOI: 10.1055/s-0040-1715474.
[9]	HU S, LIU X, GAO Y, et al. Hepatitis B virus inhibits neutrophil extracellular trap release by modulating reactive oxygen species production and autophagy[J]. J Immunol, 2019, 202( 3): 805- 815. DOI: 10.4049/jimmunol.1800871.
[10]	ZHAN X, WU R, KONG XH, et al. Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma[J]. Cancer Commun(Lond), 2023, 43( 2): 225- 245. DOI: 10.1002/cac2.12388.
[11]	POWELL EE, WONG VW, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397( 10290): 2212- 2224. DOI: 10.1016/S0140-6736(20)32511-3.
[12]	ARELAKI S, KOLETSA T, SINAKOS E, et al. Neutrophil extracellular traps enriched with IL-1β and IL-17A participate in the hepatic inflammatory process of patients with non-alcoholic steatohepatitis[J]. Virchows Arch, 2022, 481( 3): 455- 465. DOI: 10.1007/s00428-022-03330-7.
[13]	XU L, LIU X, JIA T, et al. Tanshinone IIA ameliorates nonalcoholic steatohepatitis in mice by modulating neutrophil extracellular traps and hepatocyte apoptosis[J]. Evid Based Complement Alternat Med, 2022, 2022: 5769350. DOI: 10.1155/2022/5769350.
[14]	DU J, ZHANG J, CHEN X, et al. Neutrophil extracellular traps induced by pro-inflammatory cytokines enhance procoagulant activity in NASH patients[J]. Clin Res Hepatol Gastroenterol, 2022, 46( 1): 101697. DOI: 10.1016/j.clinre.2021.101697.
[15]	WANG H, ZHANG H, WANG Y, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis[J]. J Hepatol, 2021, 75( 6): 1271- 1283. DOI: 10.1016/j.jhep.2021.07.032.
[16]	ZHANG S, ZHANG Q, WANG F, et al. Hydroxychloroquine inhibiting neutrophil extracellular trap formation alleviates hepatic ischemia/reperfusion injury by blocking TLR9 in mice[J]. Clin Immunol, 2020, 216: 108461. DOI: 10.1016/j.clim.2020.108461.
[17]	WU X, YANG Z, WANG H, et al. High-mobility group box protein-1 induces acute pancreatitis through activation of neutrophil extracellular trap and subsequent production of IL-1β[J]. Life Sci, 2021, 286: 119231. DOI: 10.1016/j.lfs.2021.119231.
[18]	TOHME S, YAZDANI HO, SUD V, et al. Computational analysis supports IL-17A as a central driver of neutrophil extracellular trap-mediated injury in liver ischemia reperfusion[J]. J Immunol, 2019, 202( 1): 268- 277. DOI: 10.4049/jimmunol.1800454.
[19]	HUANG H, TOHME S, AL-KHAFAJI AB, et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury[J]. Hepatology, 2015, 62( 2): 600- 614. DOI: 10.1002/hep.27841.
[20]	GUO J, AKAHOSHI T, MIZUTA Y, et al. Histidine-rich glycoprotein alleviates liver ischemia/reperfusion injury in mice with nonalcoholic steatohepatitis[J]. Liver Transpl, 2021, 27( 6): 840- 853. DOI: 10.1002/lt.25960.
[21]	ZHANG QG, LING S, LIU J, et al. Effect of neutrophil extracellular snare on ischemia-reperfusion injury and progress of Chinese medicine intervention[J]. J Shanghai Univ Traditional Chin Med, 2018, 32( 3): 97- 102, 108. DOI: 10.16306/j.1008-861x.2018.03.020. 张庆光, 凌霜, 刘俊, 等. 嗜中性粒细胞胞外诱捕网对缺血再灌注损伤的影响及中医药干预研究进展[J]. 上海中医药大学学报, 2018, 32( 3): 97- 102, 108. DOI: 10.16306/j.1008-861x. 2018.03.020.
[22]	ARUMUGAM S, GIRISH SUBBIAH K, KEMPARAJU K, et al. Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: Therapeutic potential of NOX2 and p38MAPK inhibitors[J]. J Cell Physiol, 2018, 233( 4): 3244- 3261. DOI: 10.1002/jcp.26167.
[23]	LLOVET JM, CASTET F, HEIKENWALDER M, et al. Immunotherapies for hepatocellular carcinoma[J]. Nat Rev Clin Oncol, 2022, 19( 3): 151- 172. DOI: 10.1038/s41571-021-00573-2.
[24]	XIAO Y, CONG M, LI J, et al. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation[J]. Cancer Cell, 2021, 39( 3): 423- 437. e 7. DOI: 10.1016/j.ccell.2020.12.012.
[25]	ZENLANDER R, HAVERVALL S, MAGNUSSON M, et al. Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma[J]. Sci Rep, 2021, 11( 1): 18025. DOI: 10.1038/s41598-021-97233-3.
[26]	KALTENMEIER CT, YAZDANI H, van der WINDT D, et al. Neutrophil extracellular traps as a novel biomarker to predict recurrence-free and overall survival in patients with primary hepatic malignancies[J]. HPB(Oxford), 2021, 23( 2): 309- 320. DOI: 10.1016/j.hpb.2020.06.012.
[27]	WANG T, ZHOU Y, ZHOU Z, et al. Secreted protease PRSS35 suppresses hepatocellular carcinoma by disabling CXCL2-mediated neutrophil extracellular traps[J]. Nat Commun, 2023, 14( 1): 1513. DOI: 10.1038/s41467-023-37227-z.
[28]	GUAN X, LU Y, ZHU H, et al. The Crosstalk between cancer cells and neutrophils enhances hepatocellular carcinoma metastasis via neutrophil extracellular traps-associated cathepsin G component: a potential therapeutic target[J]. J Hepatocell Carcinoma, 2021, 8: 451- 465. DOI: 10.2147/JHC.S303588.
[29]	YANG LY, SHEN XT, SUN HT, et al. Neutrophil extracellular traps in hepatocellular carcinoma are enriched in oxidized mitochondrial DNA which is highly pro-inflammatory and pro-metastatic[J]. J Cancer, 2022, 13( 4): 1261- 1271. DOI: 10.7150/jca.64170.
[30]	HU L, GAO L, DIRK H, et al. Regulatory effect of tumor-associated neutrophils in the development and progression of liver cancer[J]. J Clin Hepatol, 2020, 36( 9): 2100- 2102. DOI: 10.3969/j.issn.1001-5256.2020.09.2100.03. 胡雷, 高丽, Hermann Dirk, 等. 肿瘤相关中性粒细胞在肝癌发生发展中的调控作用[J]. 临床肝胆病杂志, 2020, 36( 9): 2100- 2102. DOI: 10.3969/j.issn.1001-5256.2020.09.2100.03.
[31]	CAO L, LI Q, JI LS, et al. Formation mechanism of neutrophil extracellular traps and their role in liver diseases[J]. J Clin Hepatol, 2020, 36( 1): 205- 207. DOI: 10.3969/j.issn.1001-5256.2020.01.049. 曹林, 李茜, 纪龙珊, 等. 中性粒细胞胞外诱捕网的形成机制及在肝病中的作用[J]. 临床肝胆病杂志, 2020, 36( 1): 205- 207. DOI: 10.3969/j.issn.1001-5256.2020.01.049.