高级检索
中华实验眼科杂志
期刊首页
过刊列表
高级检索
稿件发表
• 综述 •
ENGLISH ABSTRACT
补体异常活化促进年龄相关性黄斑变性发生的作用和机制
程心璇
刘祖国 [综述]
廖怿 [综述]
作者及单位信息
·
DOI： 10.3760/cma.j.cn115989-20191023-00461
Role of complement dysregulation in age-related macular degeneration
Cheng Xinxuan
Liu Zuguo
Liao Yi
Authors Info & Affiliations
Cheng Xinxuan
Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen 361000, China
Cheng Xinxuan is working at Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
Liu Zuguo
Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen 361000, China
Liao Yi
Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Fujian Engineering and Research Center of Eye Regenerative Medicine, Xiamen 361000, China
·
DOI： 10.3760/cma.j.cn115989-20191023-00461
1194
116
0
0
5
0
PDF下载
APP内阅读
摘要

年龄相关性黄斑变性(AMD)是一种常见的致盲眼病，目前依然缺乏有效的治疗手段。作为一种受到遗传、代谢及营养等多因素影响的疾病，慢性炎症反应是促进AMD发生和发展的关键因素。近年来，补体异常在AMD发生和发展中的作用受到广泛关注。其中，以CFH为代表的补体相关AMD风险基因已得到大量遗传学研究证实。采用体内和体外研究模型发现，眼内局部以及全身性的补体异常活化与Bruch膜的改变、玻璃膜疣的形成、视网膜慢性炎症以及脉络膜新生血管等AMD相关病理改变密切相关。补体因子通过激活的补体级联反应损伤视网膜细胞，导致AMD病理改变的发生。因此，补体系统已成为开发针对干性和湿性AMD新疗法的重要靶点。基于此，本综述概括总结了AMD的病理特征、补体相关的AMD风险基因，以及补体异常活化在推动AMD病程发展中的重要作用，以期为AMD治疗寻找新靶点。

年龄相关性黄斑变性;补体;玻璃膜疣;脉络膜新生血管
ABSTRACT

Age-related macular degeneration (AMD) is a common cause of blindness, which is still short of effective therapies.As a complex disease affected by genetical, metabolic and nutritional factors, a key factor to promote the occurrence and development of AMD is chronic inflammation.In recent years, the etiological role of abnormal complement activation in AMD has attracted lots of attention.Genetic analysis has identified a number of complement-related genes, especially CFH, affecting the susceptibility of AMD.Moreover, in vitro and in vivo studies have found that abnormal ocular and systemic complement activations are closely related to the pathological alterations of AMD, including Bruch membrane changes, drusen formation, chronic retinal inflammation and choroidal neovascularization.The dysregulation of complement activation cascades causes the damage of retinal cells, which eventually leads to the pathological changes of AMD.Accordingly, complement system has become a target for new anti-AMD therapy development.This review summarized the pathological characteristics of AMD, complement-related risk genes for AMD, and the role of abnormal complement activation in promoting the progression of AMD, so as to find new targets for AMD treatment.

Age-related macular degeneration;Complement;Drusen;Choroidal neovascularization
Liao Yi, Email: nc.defudabe.umxiroliyoail
Copyright by Chinese Medical Association
No content published by the journals of Chinese Medical Association may be reproduced or abridged without authorization. Please do not use or copy the layout and design of the journals without permission.
All articles published represent the opinions of the authors, and do not reflect the official policy of the Chinese Medical Association or the Editorial Board, unless this is clearly specified.
引用本文

程心璇,刘祖国,廖怿. 补体异常活化促进年龄相关性黄斑变性发生的作用和机制[J]. 中华实验眼科杂志,2022,40(12)：1186-1191.

DOI:10.3760/cma.j.cn115989-20191023-00461

PERMISSIONS

Request permissions for this article from CCC.

评价本文
*以上评分为匿名评价

版权归中华医学会所有。

未经授权，不得转载、摘编本刊文章，不得使用本刊的版式设计。

除非特别声明，本刊刊出的所有文章不代表中华医学会和本刊编委会的观点。

年龄相关性黄斑变性(age-related macular degeneration，AMD)是造成老年人不可逆视力损伤的重要原因，2040年全球AMD患者预计将增至2.88亿 [ 1 ]。AMD的临床分型可以分为早期非渗出性(干性)AMD、晚期非渗出性(萎缩性)AMD和渗出性或新生血管性(湿性)AMD [ 2 ]。干性AMD患者视力退化不明显，表现为玻璃膜疣(drusen)和/或黄斑处的视网膜色素上皮(retinal pigment epithelium，RPE)改变 [ 2 ]。其中，drusen是含有多种脂类和蛋白质的细胞外沉积物，可能导致RPE功能受损及RPE与脉络膜之间物质代谢转运障碍 [ 3 , 4 , 5 ]。干性AMD进展至晚期出现萎缩性AMD，表现为视力盲点和区域性RPE和下方感光细胞的缺失死亡，又称为地图样萎缩(geographic atrophy，GA) [ 2 ]。少数干性AMD患者在晚期转变为湿性AMD，表现为脉络膜新生血管(choroidal neovascularization，CNV) [ 2 ]。作为一种受到遗传、代谢及营养等多因素影响的疾病，慢性炎症反应是促进AMD发生和发展的关键因素 [ 6 ]。近年来，大量研究表明补体参与AMD的病理过程，补体过度激活导致的免疫损伤加速AMD进程。因此，充分认识AMD病程中补体的致病机制，并进一步开发有针对性的补体药物，对AMD的治疗具有积极的意义。
试读结束，您可以通过登录机构账户或个人账户后获取全文阅读权限。
参考文献
[1]
Wong WL , Su X , Li X ，et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040：a systematic review and meta-analysis[J/OL]．Lancet Glob Health， 2014，2(2)∶e106-116[2022－01－23]．https://pubmed.ncbi.nlm.nih.gov/25104651/. DOI： 10.1016/S2214-109X(13)70145-1 .
返回引文位置Google Scholar
百度学术
万方数据
[2]
Whitmore SS , Sohn EH , Chirco KR ，et al. Complement activation and choriocapillaris loss in early AMD：implications for pathophysiology and therapy[J]．Prog Retin Eye Res， 2015，45∶1-29. DOI： 10.1016/j.preteyeres.2014.11.005 .
返回引文位置Google Scholar
百度学术
万方数据
[3]
Khan KN , Mahroo OA , Khan RS ，et al. Differentiating drusen：drusen and drusen-like appearances associated with ageing，age-related macular degeneration，inherited eye disease and other pathological processes[J]．Prog Retin Eye Res， 2016，53∶70-106. DOI： 10.1016/j.preteyeres.2016.04.008 .
返回引文位置Google Scholar
百度学术
万方数据
[4]
Nita M , Strzaka-Mrozik B , Grzybowski A ，et al. Age-related macular degeneration and changes in the extracellular matrix[J]．Med Sci Monit， 2014，20∶1003-1016. DOI： 10.12659/MSM.889887 .
返回引文位置Google Scholar
百度学术
万方数据
[5]
Crabb JW . The proteomics of drusen[J]．Cold Spring Harb Perspect Med， 2014，4(7)∶a017194[2022－01－23]．https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066642/. DOI： 10.1101/cshperspect.a017194 .
返回引文位置Google Scholar
百度学术
万方数据
[6]
Ferris FL 3rd , Wilkinson CP , Bird A ，et al. Clinical classification of age-related macular degeneration[J]．Ophthalmology， 2013，120(4)∶844-851. DOI： 10.1016/j.ophtha.2012.10.036 .
返回引文位置Google Scholar
百度学术
万方数据
[7]
Luo C , Chen M , Xu H ．Complement gene expression and regulation in mouse retina and retinal pigment epithelium/choroid[J]．Mol Vis， 2011，17∶1588-1597.
返回引文位置Google Scholar
百度学术
万方数据
[8]
Perez VL , Caspi RR . Immune mechanisms in inflammatory and degenerative eye disease[J]．Trends Immunol， 2015，36(6)∶354-363. DOI： 10.1016/j.it.2015.04.003 .
返回引文位置Google Scholar
百度学术
万方数据
[9]
Ding JD , Kelly U , Groelle M ，et al. The role of complement dysregulation in AMD mouse models[J]．Adv Exp Med Biol， 2014，801∶13-219. DOI： 10.1007/978-1-4614-3209-8_28 .
返回引文位置Google Scholar
百度学术
万方数据
[10]
Tan LX , Toops KA , Lakkaraju A ．Protective responses to sublytic complement in the retinal pigment epithelium[J]．Proc Natl Acad Sci U S A， 2016，113(31)∶8789-8794. DOI： 10.1073/pnas.1523061113 .
返回引文位置Google Scholar
百度学术
万方数据
[11]
Edwards AO , Ritter R 3rd , Abel KJ ，et al. Complement factor H polymorphism and age-related macular degeneration[J]．Science， 2005，308(5720)∶421-424. DOI： 10.1126/science.1110189 .
返回引文位置Google Scholar
百度学术
万方数据
[12]
Klein RJ , Zeiss C , Chew EY ，et al. Complement factor H polymorphism in age-related macular degeneration[J]．Science， 2005，308(5720)∶385-389. DOI： 10.1126/science.1109557 .
返回引文位置Google Scholar
百度学术
万方数据
[13]
Hageman GS , Anderson DH , Johnson LV ，et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration[J]．Proc Natl Acad Sci U S A， 2005，102(20)∶7227-7232. DOI： 10.1073/pnas.0501536102 .
返回引文位置Google Scholar
百度学术
万方数据
[14]
Calippe B , Augustin S , Beguier F ，et al. Complement factor H inhibits CD47-mediated resolution of inflammation[J]．Immunity， 2017，46(2)∶261-272. DOI： 10.1016/j.immuni.2017.01.006 .
返回引文位置Google Scholar
百度学术
万方数据
[15]
Toomey CB , Johnson LV , Bowes Rickman C ．Complement factor H in AMD：bridging genetic associations and pathobiology[J]．Prog Retin Eye Res， 2018，62∶38-57. DOI： 10.1016/j.preteyeres.2017.09.001 .
返回引文位置Google Scholar
百度学术
万方数据
[16]
Chirco KR , Flamme-Wiese MJ , Wiley JS ，et al. Evaluation of serum and ocular levels of membrane attack complex and C-reactive protein in CFH-genotyped human donors[J]．Eye (Lond)， 2018，32(11)∶1740-1742. DOI： 10.1038/s41433-018-0170-8 .
返回引文位置Google Scholar
百度学术
万方数据
[17]
Triebwasser MP , Roberson ED , Yu Y ，et al. Rare variants in the functional domains of complement factor H are associated with age-related macular degeneration[J]．Invest Ophthalmol Vis Sci， 2015，56(11)∶6873-6878. DOI： 10.1167/iovs.15-17432 .
返回引文位置Google Scholar
百度学术
万方数据
[18]
Gold B , Merriam JE , Zernant J ，et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration[J]．Nat Genet， 2006，38(4)∶458-462. DOI： 10.1038/ng1750 .
返回引文位置Google Scholar
百度学术
万方数据
[19]
Maller JB , Fagerness JA , Reynolds RC ，et al. Variation in complement factor 3 is associated with risk of age-related macular degeneration[J]．Nat Genet， 2007，39(10)∶1200-1201. DOI： 10.1038/ng2131 .
返回引文位置Google Scholar
百度学术
万方数据
[20]
Seddon JM , Yu Y , Miller EC ，et al. Rare variants in CFI，C3 and C9 are associated with high risk of advanced age-related macular degeneration[J]．Nat Genet， 2013，45(11)∶1366-1370. DOI： 10.1038/ng.2741 .
返回引文位置Google Scholar
百度学术
万方数据
[21]
Fagerness JA , Maller JB , Neale BM ，et al. Variation near complement factor I is associated with risk of advanced AMD[J]．Eur J Hum Genet， 2009，17(1)∶100-104. DOI： 10.1038/ejhg.2008.140 .
返回引文位置Google Scholar
百度学术
万方数据
[22]
Fritsche LG , Igl W , Bailey JN ，et al. A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants[J]．Nat Genet， 2016，48(2)∶134-143. DOI： 10.1038/ng.3448 .
返回引文位置Google Scholar
百度学术
万方数据
[23]
Hughes AE , Orr N , Esfandiary H ，et al. A common CFH haplotype，with deletion of CFHR1 and CFHR3，is associated with lower risk of age-related macular degeneration[J]．Nat Genet， 2006，38(10)∶1173-1177. DOI： 10.1038/ng1890 .
返回引文位置Google Scholar
百度学术
万方数据
[24]
Fritsche LG , Fariss RN , Stambolian D ，et al. Age-related macular degeneration：genetics and biology coming together[J]．Annu Rev Genomics Hum Genet， 2014，15∶151-171. DOI： 10.1146/annurev-genom-090413-025610 .
返回引文位置Google Scholar
百度学术
万方数据
[25]
Geerlings MJ , Kremlitzka M , Bakker B ，et al. The functional effect of rare variants in complement genes on C3b degradation in patients with age-related macular degeneration[J]．JAMA Ophthalmol， 2017，135(1)∶39-46. DOI： 10.1001/jamaophthalmol.2016.4604 .
返回引文位置Google Scholar
百度学术
万方数据
[26]
Fernandez-Godino R , Pierce EA , Garland DL . Extracellular matrix alterations and deposit formation in AMD[J]．Adv Exp Med Biol， 2016，854∶53-58. DOI： 10.1007/978-3-319-17121-0_8 .
返回引文位置Google Scholar
百度学术
万方数据
[27]
Fernandez-Godino R , Bujakowska KM , Pierce EA . Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway[J]．Hum Mol Genet， 2018，27(1)∶147-159. DOI： 10.1093/hmg/ddx392 .
返回引文位置Google Scholar
百度学术
万方数据
[28]
Clark SJ , Bishop PN . The eye as a complement dysregulation hotspot[J]．Semin Immunopathol， 2018，40(1)∶65-74. DOI： 10.1007/s00281-017-0649-6 .
返回引文位置Google Scholar
百度学术
万方数据
[29]
Crabb JW , Miyagi M , Gu X ，et al. Drusen proteome analysis：an approach to the etiology of age-related macular degeneration[J/OL]．Proc Natl Acad Sci U S A， 2002，99(23)∶14682-14687[2022－01－23]．https://pubmed.ncbi.nlm.nih.gov/12391305/. DOI： 10.1073/pnas.222551899 .
返回引文位置Google Scholar
百度学术
万方数据
[30]
Taylor RL , Poulter JA , Downes SM ，et al. Loss-of-function mutations in the CFH gene affecting alternatively encoded factor H-like 1 protein cause dominant early-onset macular drusen [J]．Ophthalmology， 2019，126(10)∶1410-1421. DOI： 10.1016/j.ophtha.2019.03.013 .
返回引文位置Google Scholar
百度学术
万方数据
[31]
Landowski M , Kelly U , Klingeborn M ，et al. Human complement factor H Y402H polymorphism causes an age-related macular degeneration phenotype and lipoprotein dysregulation in mice[J]．Proc Natl Acad Sci U S A， 2019，116(9)∶3703-3711. DOI： 10.1073/pnas.1814014116 .
返回引文位置Google Scholar
百度学术
万方数据
[32]
Kauppinen A , Paterno JJ , Blasiak J ，et al. Inflammation and its role in age-related macular degeneration[J]．Cell Mol Life Sci， 2016，73(9)∶1765-1786. DOI： 10.1007/s00018-016-2147-8 .
返回引文位置Google Scholar
百度学术
万方数据
[33]
Asgari E , Le Friec G , Yamamoto H ，et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation[J]．Blood， 2013，122(20)∶3473-3481. DOI： 10.1182/blood-2013-05-502229 .
返回引文位置Google Scholar
百度学术
万方数据
[34]
Brandstetter C , Holz FG , Krohne TU . Complement component C5a primes retinal pigment epithelial cells for inflammasome activation by lipofuscin-mediated photooxidative damage[J/OL]．J Biol Chem， 2015，290(52)∶31189-31198[2021－01－23]．https://pubmed.ncbi.nlm.nih.gov/26565031/. DOI： 10.1074/jbc.M115.671180 .
返回引文位置Google Scholar
百度学术
万方数据
[35]
Brandstetter C , Patt J , Holz FG ，et al. Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis[J]．J Photochem Photobiol B， 2016，161∶177-183. DOI： 10.1016/j.jphotobiol.2016.05.018 .
返回引文位置Google Scholar
百度学术
万方数据
[36]
Kunchithapautham K , Rohrer B ．Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers[J/OL]．J Biol Chem， 2011，286(27)∶23717-23724[2021－01－24]．https://pubmed.ncbi.nlm.nih.gov/21566137/. DOI： 10.1074/jbc.M110.214593 .
返回引文位置Google Scholar
百度学术
万方数据
[37]
Long Q , Cao X , Bian A ，et al. C3a increases VEGF and decreases PEDF mRNA levels in human retinal pigment epithelial cells[J/OL]．Biomed Res Int， 2016，2016∶6958752[2022－01－24]．https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055919/. DOI： 10.1155/2016/6958752 .
返回引文位置Google Scholar
百度学术
万方数据
[38]
Coughlin B , Schnabolk G , Joseph K ，et al. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells[J/OL]．Sci Rep， 2016，6∶23794[2022－01－24]．https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814842/. DOI： 10.1038/srep23794 .
返回引文位置Google Scholar
百度学术
万方数据
[39]
Brockmann C , Brockmann T , Dege S ，et al. Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice[J]．Graefe's Arch Clin Exp Ophthalmol， 2015，253(10)∶1695-1704. DOI： 10.1007/s00417-015-3041-z .
返回引文位置Google Scholar
百度学术
万方数据
[40]
Bora PS , Sohn JH , Cruz JM ，et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization[J]．J Immunol， 2005，174(1)∶491-497. DOI： 10.4049/jimmunol.174.1.491 .
返回引文位置Google Scholar
百度学术
万方数据
[41]
Liu J , Jha P , Lyzogubov VV ，et al. Relationship between complement membrane attack complex，chemokine (C-C motif) ligand 2 (CCL2) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization[J/OL]．J Biol Chem， 2011，286(23)∶20991-21001[2022－01－25]．https://pubmed.ncbi.nlm.nih.gov/21515678/. DOI： 10.1074/jbc.M111.226266 .
返回引文位置Google Scholar
百度学术
万方数据
[42]
Schnabolk G , Beon MK , Tomlinson S ，et al. New insights on complement inhibitor CD59 in mouse laser-induced choroidal neovascularization：mislocalization after injury and targeted delivery for protein replacement[J]．J Ocul Pharmacol Ther， 2017，33(5)∶400-411. DOI： 10.1089/jop.2016.0101 .
返回引文位置Google Scholar
百度学术
万方数据
[43]
de Jong S , Tang J , Clark SJ . Age-related macular degeneration：a disease of extracellular complement amplification[J/OL]．Immunol Rev， 2022[2022－11－03]．https://pubmed.ncbi.nlm.nih.gov/36223117/[published online ahead of print]．
返回引文位置Google Scholar
百度学术
万方数据
[44]
Parsons N , Annamalai B , Obert E ，et al. Inhibition of the alternative complement pathway accelerates repair processes in the murine model of choroidal neovascularization[J]．Mol Immunol， 2019，108∶8-12. DOI： 10.1016/j.molimm.2019.02.001 .
返回引文位置Google Scholar
百度学术
万方数据
[45]
Schnabolk G , Parsons N , Obert E ，et al. Delivery of CR2-fH using AAV vector therapy as treatment strategy in the mouse model of choroidal neovascularization[J]．Mol Ther Methods Clin Dev， 2018，9∶1-11. DOI： 10.1016/j.omtm.2017.11.003 .
返回引文位置Google Scholar
百度学术
万方数据
[46]
Warwick A , Khandhadia S , Ennis S ，et al. Age-related macular degeneration：a disease of systemic or local complement dysregulation？[J]．J Clin Med， 2014，3(4)∶1234-1257. DOI： 10.3390/jcm3041234 .
返回引文位置Google Scholar
百度学术
万方数据
[47]
Lechner J , Chen M , Hogg RE ，et al. Higher plasma levels of complement C3a，C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration：complement activation in AMD[J/OL]．Immun Ageing， 2016，13∶4[2022－01－25]．https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754842/. DOI： 10.1186/s12979-016-0060-5 .
返回引文位置Google Scholar
百度学术
万方数据
[48]
Lin JB , Serghiou S , Miller JW ，et al. Systemic complement activation profiles in nonexudative age-related macular degeneration：a systematic review[J/OL]．Ophthalmol Sci， 2022，2(2)∶100118[2022－11－03]．https://pubmed.ncbi.nlm.nih.gov/35614900/. DOI： 10.1016/j.xops.2022.100118 .
返回引文位置Google Scholar
百度学术
万方数据
[49]
Bora NS , Kaliappan S , Jha P ，et al. CD59，a complement regulatory protein，controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration[J]．J Immunol， 2007，178(3)∶1783-1790. DOI： 10.4049/jimmunol.178.3.1783 .
返回引文位置Google Scholar
百度学术
万方数据
[50]
Mastellos DC , Yancopoulou D , Kokkinos P ，et al. Compstatin：a C3-targeted complement inhibitor reaching its prime for bedside intervention[J]．Eur J Clin Invest， 2015，45(4)∶423-440. DOI： 10.1111/eci.12419 .
返回引文位置Google Scholar
百度学术
万方数据
[51]
Yehoshua Z , de Amorim Garcia Filho CA , Nunes RP ，et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration：the COMPLETE study[J]．Ophthalmology， 2014，121(3)∶693-701. DOI： 10.1016/j.ophtha.2013.09.044 .
返回引文位置Google Scholar
百度学术
万方数据
[52]
Holz FG , Sadda SR , Busbee B ，et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration：chroma and spectri phase 3 randomized clinical trials[J]．JAMA Ophthalmol， 2018，136(6)∶666-677. DOI： 10.1001/jamaophthalmol.2018.1544 .
返回引文位置Google Scholar
百度学术
万方数据
[53]
Wu J , Sun X ．Complement system and age-related macular degeneration：drugs and challenges[J]．Drug Des Devel Ther， 2019，13∶2413-2425. DOI： 10.2147/DDDT.S206355 .
返回引文位置Google Scholar
百度学术
万方数据
[54]
Tran M , Khalid M , Pébay A ，et al. Screening of CRISPR/Cas base editors to target the AMD high-risk Y402H complement factor H variant[J]．Mol Vis， 2019，25∶174-182.
返回引文位置Google Scholar
百度学术
万方数据
备注信息
A
廖怿，Email： nc.defudabe.umxiroliyoail
B
所有作者均声明不存在利益冲突
C
国家重点研发计划项目 (2019YFA0111200、2018YFA0107304、2018YFA0107301)
国家自然科学基金项目 (81700864)
福建省自然科学基金面上项目 (2016J01412)
福建省中青年教师教育科研项目 (JAT160011)
评论 （0条）
注册
登录
时间排序
暂无评论，发表第一条评论抢沙发
MedAI助手（体验版）
文档即答
智问智答
机器翻译
回答内容由人工智能生成，我社无法保证其准确性和完整性，该生成内容不代表我们的态度或观点，仅供参考。
生成快照
文献快照

你好，我可以帮助您更好的了解本文，请向我提问您关注的问题。

0/2000

《中华医学会杂志社用户协议》 | 《隐私政策》

《SparkDesk 用户协议》 | 《SparkDesk 隐私政策》

网信算备340104764864601230055号 | 网信算备340104726288401230013号

技术支持：

历史对话
本文全部
还没有聊天记录
设置
模式
纯净模式沉浸模式
字号
小中大