靶向自噬缓解肝缺血再灌注损伤的研究进展

李振; 王科; 王凯强; 俞科贤

doi:10.3969/j.issn.1001-5256.2022.01.037

靶向自噬缓解肝缺血再灌注损伤的研究进展

DOI: 10.3969/j.issn.1001-5256.2022.01.037

李振¹,
王科¹,
王凯强¹,
俞科贤^2, ,

1.
青海大学研究生院，西宁 810016
2.
青海大学医学院中医学院，西宁 810016

基金项目:

国家中医药管理局——全国中医药创新骨干人才培训项目 (Chinese Medicine Education Letter〔2019〕 No.128);

教育部“春晖计划”科技项目 (Z2017038)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：李振负责课题设计，资料分析，撰写论文；李振、王科、王凯强参与收集数据，修改论文；俞科贤、李振负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
俞科贤，ykx0421@163.com

作者说明：李振和王科同为第一作者

计量
- 文章访问数: 412
- HTML全文浏览量: 146
- PDF下载量: 41
- 被引次数: 0
出版历程
- 收稿日期: 2021-06-20
- 录用日期: 2021-08-13
- 出版日期: 2022-01-20

Research advances in targeting autophagy to alleviate hepatic ischemia-reperfusion injury

1.
Graduate School of Qinghai University, Xining 810016, China
2.
School of Traditional Chinese Medicine, Medical College of Qinghai University, Xining 810016, China

Research funding:

State Administration of Traditional Chinese Medicine-National Training Program for Innovative Key Talents of Traditional Chinese Medicine (Chinese Medicine Education Letter〔2019〕 No.128);

Science and Technology Project of "Chunhui Plan" of Ministry of Education (Z2017038)

摘要

摘要: 肝缺血再灌注损伤(HIRI)是肝切除和肝移植术后常见的临床问题，是导致移植术后肝功能障碍和肝功能衰竭的主要原因。近年来，自噬介导的途径成为缓解HIRI的研究热点。自噬是指细胞通过将大量细胞质、受损细胞器等底物运输到溶酶体内进行消化降解以不断更新重塑再利用细胞的过程。本文从基因、蛋白、信号通路、炎症反应、氧化应激反应、线粒体及内质网应激等方面总结了靶向自噬途径缓解HIRI相关机制的研究进展，并围绕研究中存在的问题进行了讨论和展望，以期为今后通过靶向自噬途径缓解HIRI的研究提供理论支持。
- 自噬 /
- 再灌注损伤 /
- 氧化性应激
Abstract: Hepatic ischemia-reperfusion injury (HIRI) is a common clinical problem after hepatectomy and liver transplantation and is the main cause of liver dysfunction and liver failure after transplantation. In recent years, autophagy-mediated pathways have become a research hotspot in alleviating HIRI. Autophagy refers to the process in which a large number of substrates such as cytoplasm and damaged organelles are transported into lysosomes for digestion and degradation, so as to constantly renew, reshape, and reuse cells. This article summarizes the research advances in the mechanism of targeting autophagy to alleviate HIRI from the aspects of gene, protein, signaling pathway, inflammatory response, oxidative stress, and mitochondrial and endoplasmic reticulum stress, as well as existing problems and prospects in research, in order to provide theoretical support for the future research on alleviating HIRI by targeting autophagy.
- Autophagy /
- Reperfusion Injury /
- Oxidative Stress

HTML全文

图 1 提高HIRI中自噬水平的机制

下载: 全尺寸图片幻灯片

图 2 降低HIRI中自噬水平的机制

下载: 全尺寸图片幻灯片

参考文献(40)

[1]	HUA S, MA M, FEI X, et al. Glycyrrhizin attenuates hepatic ischemia-reperfusion injury by suppressing HMGB1-dependent GSDMD-mediated kupffer cells pyroptosis[J]. Int Immunopharmacol, 2019, 68: 145-155. DOI: 10.1016/j.intimp.2019.01.002.
[2]	GE Y, ZHANG Q, JIAO Z, et al. Adipose-derived stem cells reduce liver oxidative stress and autophagy induced by ischemia-reperfusion and hepatectomy injury in swine[J]. Life Sci, 2018, 214: 62-69. DOI: 10.1016/j.lfs.2018.10.054.
[3]	HILL SM, WROBEL L, RUBINSZTEIN DC. Post-translational modifications of Beclin 1 provide multiple strategies for autophagy regulation[J]. Cell Death Differ, 2019, 26(4): 617-629. DOI: 10.1038/s41418-018-0254-9.
[4]	XIA Y, LI J, CHEN K, et al. Bergenin attenuates hepatic fibrosis by regulating autophagy mediated by the PPAR-γ/TGF-β pathway[J]. PPAR Res, 2020, 2020(14): 1-13. DOI: 10.1155/2020/6694214.
[5]	CACCAMO A, FERREIRA E, BRANCA C, et al. Retraction note: p62 improves AD-like pathology by increasing autophagy[J]. Mol Psychiatry, 2021, 26(7): 3664. DOI: 10.1038/s41380-020-0854-x.
[6]	YANG LC, ZHANG XY, PAN NB, et al. Effect of rapamycin on the expression of autophagy-related proteins Unc-51 like autophagy activating kinase 1 and microtubule-associated protein 1 light chain 3 in hepatic ischemia-reperfusion injury and its significance[J]. J Clin Hepatol, 2019, 35(10): 2261-2265. DOI: 10.3969/j.issn.1001-5256.2019.10.026. 杨龙灿, 张旭阳, 潘宁波, 等. 雷帕霉素在肝脏缺血再灌注损伤中对自噬相关蛋白ULK1、LC3表达的影响[J]. 临床肝胆病杂志, 2019, 35(10): 2261-2265. DOI: 10.3969/j.issn.1001-5256.2019.10.026.
[7]	XIAO X, LIU D, CHEN S, et al. Sevoflurane preconditioning activates HGF/Met-mediated autophagy to attenuate hepatic ischemia-reperfusion injury in mice[J]. Cell Signal, 2021, 82(2017): 109966. DOI: 10.1016/j.cellsig.2021.109966.
[8]	XIONG C, DU Z, ZHU Y, et al. Mycophenolate mofetil preconditioning protects mouse liver against ischemia/reperfusion injury in wild type and toll-like receptor 4 knockout mice[J]. Transpl Immunol, 2020, 65(4): 101357. DOI: 10.1016/j.trim.2020.101357.
[9]	ZHOU H, LI L, SUN H, et al. Remote ischemic preconditioning attenuates hepatic ischemia/reperfusion injury after hemorrhagic shock by increasing autophagy[J]. Int J Med Sci, 2021, 18(4): 873-882. DOI: 10.7150/ijms.51268.
[10]	LIU A, WANG W, LU Z, et al. Mild hypothermia pretreatment extenuates liver ischemia-reperfusion injury through Rab7-mediated autophagosomes-lysosomes fusion[J]. Biochem Biophys Res Commun, 2021, 550: 15-21. DOI: 10.1016/j.bbrc.2021.02.125.
[11]	KOU X, ZHU J, XIE X, et al. The protective effect of glycyrrhizin on hepatic ischemia-reperfusion injury in rats and possible related signal pathway[J]. Iran J Basic Med Sci, 2020, 23(9): 1232-1238. DOI: 10.22038/ijbms.2020.44101.10334.
[12]	ZHANG J, CHENG P, DAI W, et al. Fenofibrate ameliorates hepatic ischemia/reperfusion injury in mice: Involvements of apoptosis, autophagy, and PPAR-α activation[J]. PPAR Res, 2021, 2021: 6658944. DOI: 10.1155/2021/6658944.
[13]	CHEN QS, SHEN A, DAI JW, et al. IL37 overexpression inhibits autophagy and apoptosis induced by hepatic ischemia reperfusion injury via modulating AMPK/mTOR/ULLK1 signalling pathways[J]. Life Sci, 2021, 276: 119424. DOI: 10.1016/j.lfs.2021.119424.
[14]	ZHU S, ZHANG J, ZHANG L, et al. Inhibition of Kupffer cell autophagy abrogates nanoparticle-induced liver injury[J]. Adv Healthc Mater, 2017, 6(9): 1601252. DOI: 10.1002/adhm.201601252.
[15]	DENG J, FENG J, LIU T, et al. Beraprost sodium preconditioning prevents inflammation, apoptosis, and autophagy during hepatic ischemia-reperfusion injury in mice via the P38 and JNK pathways[J]. Drug Des Devel Ther, 2018, 12: 4067-4082. DOI: 10.2147/DDDT.S182292.
[16]	XU S, NIU P, CHEN K, et al. The liver protection of propylene glycol alginate sodium sulfate preconditioning against ischemia reperfusion injury: Focusing MAPK pathway activity[J]. Sci Rep, 2017, 7(1): 15175. DOI: 10.1038/s41598-017-15521-3.
[17]	JI J, WU L, FENG J, et al. Cafestol preconditioning attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by inhibiting ERK/PPARγ pathway[J]. Int Immunopharmacol, 2020, (84): 106529. DOI: 10.1016/j.intimp.2020.106529.
[18]	NI M, ZHOU H, ZHANG J, et al. Isoform- and cell type-specific roles of glycogen synthase kinase 3 N-terminal serine phosphorylation in liver ischemia reperfusion injury[J]. J Immunol, 2020, 205(4): 1147-1156. DOI: 10.4049/jimmunol.2000397.
[19]	LI S, YI Z, DENG M, et al. TSLP protects against liver I/R injury via activation of the PI3K/Akt pathway[J]. JCI Insight, 2019, 4(22): e129013. DOI: 10.1172/jci.insight.129013.
[20]	WANG Z, WANG H, CHEN X, et al. Inhibiting ATP6V0D2 aggravates liver ischemia-reperfusion injury by promoting NLRP3 activation via impairing autophagic flux independent of Notch1/Hes1[J]. J Immunol Res, 2021, 2021(8): 1-16. DOI: 10.1155/2021/6670495.
[21]	WANG Z, HAN S, CHEN X, et al. Eva1a inhibits NLRP3 activation to reduce liver ischemia-reperfusion injury via inducing autophagy in kupffer cells[J]. Mol Immunol, 2021, 132: 82-92. DOI: 10.1016/j.molimm.2021.01.028.
[22]	ZHANG ZY, BAO XL, CONG YY, et al. Autophagy in age-related macular degeneration: A regulatory mechanism of oxidative stress[J]. Oxid Med Cell Longev, 2020, 2020(149): 1-13. DOI: 10.1155/2020/2896036.
[23]	GUO J, ZHANG T, GU J, et al. Oleic acid protects against hepatic ischemia and reperfusion injury in mice by inhibiting AKT/mTOR pathways[J]. Oxid Med Cell Longev, 2019, 2019: 4842592. DOI: 10.1155/2019/4842592.
[24]	RUAN W, LIU Q, CHEN C, et al. Limb remote ischemic preconditioning attenuates liver ischemia reperfusion injury by activating autophagy via modulating PPAR-γ pathway[J]. J Cent South Univ (Med Sci), 2016, 41(9): 918-928. DOI: 10.11817/j.issn.1672-7347.2016.09.006.
[25]	PU T, LIAO XH, SUN H, et al. Augmenter of liver regeneration regulates autophagy in renal ischemia-reperfusion injury via the AMPK/mTOR pathway[J]. Apoptosis, 2017, 22(7): 955-969. DOI: 10.1007/s10495-017-1370-6.
[26]	BHOGAL RH, WESTON CJ, VELDUIS S, et al. The reactive oxygen species-mitophagy signaling pathway regulates liver endothelial cell survival during ischemia/reperfusion injury[J]. Liver Transpl, 2018, 24(10): 1437-1452. DOI: 10.1002/lt.25313.
[27]	LIU Z, YE S, ZHONG X, et al. Pretreatment with the ALDH2 activator Alda-1 protects rat livers from ischemia/reperfusion injury by inducing autophagy[J]. Mol Med Rep, 2020, 22(3): 2373-2385. DOI: 10.3892/mmr.2020.11312.
[28]	BAI G, LI H, GE Y, et al. Influence of hydrogen-rich saline on hepatocyte autophagy during laparoscopic liver ischaemia-reperfusion combined resection injury in miniature pigs[J]. J Vet Res, 2018, 62(3): 395-403. DOI: 10.2478/jvetres-2018-0056.
[29]	LIU DQ, CHEN SP, SUN J, et al. Berberine protects against ischemia-reperfusion injury: A review of evidence from animal models and clinical studies[J]. Pharmacol Res, 2019, 148: 104385. DOI: 10.1016/j.phrs.2019.104385.
[30]	KUCK JL, OBIAKO BO, GORODNYA OM, et al. Mitochondrial DNA damage-associated molecular patterns mediate a feed-forward cycle of bacteria-induced vascular injury in perfused rat lungs[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 308(10): L1078-L1085. DOI: 10.1152/ajplung.00015.2015.
[31]	ZHOU J, HU B, JI LW, et al. Research progress on the effect of traditional Chinese medicine to mito-chondrial autophagy[J]. China Med Herald, 2021, 18(22): 50-54. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202122011.htm 周俊, 胡犇, 戢力维, 等. 中药对线粒体自噬影响的研究进展[J]. 中国医药导报, 2021, 18(22): 50-54. https://www.cnki.com.cn/Article/CJFDTOTAL-YYCY202122011.htm
[32]	CHENG Z, GUO C. Pemafibrate pretreatment attenuates apoptosis and autophagy during hepatic ischemia-reperfusion injury by modulating JAK2/STAT3β/PPARα pathway[J]. PPAR Res, 2021, 2021: 6632137. DOI: 10.1155/2021/6632137.
[33]	WANG Y, NI Q, YE Q, et al. Tanshinone ⅡA activates autophagy to reduce liver ischemia-reperfusion injury by MEK/ERK/mTOR pathway[J]. Pharmazie, 2018, 73(7): 396-401. DOI: 10.1691/ph.2018.7509.
[34]	NING XJ, YAN X, WANG YF, et al. Parkin deficiency elevates hepatic ischemia/reperfusion injury accompanying decreased mitochondrial autophagy, increased apoptosis, impaired DNA damage repair and altered cell cycle distribution[J]. Mol Med Rep, 2018, 18(6): 5663-5668. DOI: 10.3892/mmr.2018.9606.
[35]	XU M, HANG H, HUANG M, et al. DJ-1 deficiency in hepatocytes improves liver ischemia-reperfusion injury by enhancing mitophagy[J]. Cell Mol Gastroenterol Hepatol, 2021, 12(2): 567-584. DOI: 10.1016/j.jcmgh.2021.03.007.
[36]	QI Z, CHEN L. Endoplasmic reticulum stress and autophagy[J]. Adv Exp Med Biol, 2019, 1206: 167-177. DOI: 10.1007/978-981-15-0602-4_8.
[37]	PARK S, AINTABLIAN A, COUPE B, et al. The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates[J]. Nat Commun, 2020, 11(1): 1914. DOI: 10.1038/s41467-020-15624-y.
[38]	ZHOU H, ZHU J, YUE S, et al. The dichotomy of endoplasmic reticulum stress response in liver ischemia-reperfusion injury[J]. Transplantation, 2016, 100(2): 365-372. DOI: 10.1097/TP.0000000000001032.
[39]	RUAN Z, LIANG M, DENG X, et al. Exogenous hydrogen sulfide protects fatty liver against ischemia-reperfusion injury by regulating endoplasmic reticulum stress-induced autophagy in macrophage through mediating the class A scavenger receptor pathway in rats[J]. Cell Biol Int, 2019. DOI: 10.1002/cbin.11234.[Online ahead of print]
[40]	ZHANG N, SHENG M, WU M, et al. Berberine protects steatotic donor undergoing liver transplantation via inhibiting endoplasmic reticulum stress-mediated reticulophagy[J]. Exp Biol Med (Maywood), 2019, 244(18): 1695-1704. DOI: 10.1177/1535370219878651.