（成都中医药大学眼科学院；四川成都610000）
[摘要]：随着糖尿病(diabetes mellitus, DM)患病率的升高，糖尿病性视网膜病变(Diabetic retinopathy,DR)已成为危害全球公共卫生健康的疾病。近年来，在DR病因病机方面虽然取得了可喜的发展，但是并未完全阐释。DR发病机制复杂，诸多影响因素。本文将从炎症因子、免疫应答、氧化应激、多元醇通路等方面对DR西医发病机制进行综述,以利于早期发现，早期治疗和延缓DR进展。
[关键词]：糖尿病，糖尿病视网膜病变，发病机制
Advances in research on pathogenesis of Chinese and Western medicine for diabetic retinopathy
LILINJUAN YOUYINGFAN SUXIAOJUAN JIANGYI CHENJIALI TANRONG
College of Ophthalmology, Chengdu University of Traditional Chinese Medicine
[Abstract]: With the increasing prevalence of diabetes mellitus (DM), Diabetic retinopathy (DR) has become a disease that jeopardizes global public health. In recent years, although the development of DR etiology and pathogenesis has achieved gratifying development, it has not been fully explained. The pathogenesis of DR is complex and has many influencing factors. This article reviews the pathogenesis of DR from the aspects of inflammatory factors, immune response, oxidative stress and polyol pathway, in order to facilitate early detection, early treatment and delay DR progression.
[Keywords]:Diabetes，Diabetes retinopathy ，Pathogenesis；
糖尿病(diabetes mellitus, DM) 是一种代谢性紊乱性疾病,可引起人体各组织器官慢性进行性病变，如糖尿病肾病、糖尿病周围神经病变、DR等。 DR是DM的主要并发症之一。在过去的二十年中，已成为世界上最困难的健康问题之一，全球总体患病率为34.6%[[[] Yau JW, Rogers SL, Kawasaki R. Global prevalence and major risk factors of diabetic retinopathy[J].Diabetes Care ,2012,35(3):556-564. ]]，我国患病率波动于16％-41.3％[[[] 崔颖.广东省东莞市糖尿病视网膜病变流行病学研究[D].广州:南方医科大学,2013:2.]]。据估计，有一半未经治疗的增殖性视网膜病变患者将在五年内失明[[[] Ferris FL. III Results of 20 years of research on the treatment of diabetic retinopathy[J]. Prev Med,1994, 23(5), 740-742.
]]。而目前DR的发病机制还尚未完全阐明，目前研究表明其发病机制大多与炎症因子、免疫应答、氧化应激、多元醇通路，糖基化终末产物、生长因子，蛋白激酶C激活及自噬等相关。现将其综述如下。
1.发病机制
1.1 炎症因子及免疫应答与DR
研究表明炎症因子有助于DR的病理改变，包括血 - 视网膜屏障（Blood retinal barrier,BRB）破坏，视网膜新生血管形成，视网膜谷氨酸代谢功能障碍和视网膜神经细胞凋亡[[[]Adamis Anthony P,Berman Adrienne J,Immunological mechanisms in the pathogenesis of diabetic retinopathy.[J] .Semin Immunopathol, 2008, 30: 65-84. ]][[[] Huang Hu,Gandhi Jarel K,Zhong Xiufeng et al. TNFalpha is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis.[J] .Invest. Ophthalmol. Vis. Sci., 2011, 52: 1336-44.]][[[] Shen Xi,Xie Bing,Cheng Yu et al. Effect of pigment epithelium derived factor on the expression of glutamine synthetase in early phase of experimental diabetic retinopathy.[J] .Ocul. Immunol. Inflamm., 2011, 19: 246-54.]]。白细胞介素17(interleukin-17,IL-17）为DR早期调节炎症的细胞因子之一。其家族中IL-17A是近年来备受关注的一种特殊细胞因子[[[] Teunissen M B,Koomen C W,de Waal Malefyt R et al. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes.[J] .J. Invest. Dermatol., 1998, 111: 645-9.]]。有研究表明IL17A可能对自身免疫性糖尿病的病程产生重大影响[[[] Semeran Kornel,Paw?owski Przemys?aw,Lisowski ?ukasz et al. Plasma levels of IL-17, VEGF, and adrenomedullin and S-cone dysfunction of the retina in children and adolescents without signs of retinopathy and with varied duration of diabetes.[J] .Mediators Inflamm., 2013, 2013: 274726.]]。卞征等通过动物实验证明了高糖下视网膜表达IL-17A,从而激动的Act1（NF-kB activator 1,Act1）信号通路下游的信号通路,使Muller细胞的激动，导致其细胞出现功能的障碍。也证实了IL-17A可以加剧节细胞的凋亡以及视网膜血管渗漏等病理变化[[[] 卞征. 白介素和糖尿病视网膜病变的关系[D].南京医科大学,2017.]]。在短期高糖、缺氧等刺激下，视网膜生理学短暂失衡，免疫应答的快速激活将诱导组织稳态和功能的恢复。然而，在持续高糖及缺氧等刺激下，炎症反应的慢性过度激活可导致破坏性的组织重塑[[[] Chen Mei,Xu Heping,Parainflammation, chronic inflammation, and age-related macular degeneration.[J] .J. Leukoc. Biol., 2015, 98: 713-25.]]。此外，补体因子作为炎性体组装的增强触发因素，可以导致促炎细胞因子pro-IL-1b和pro-IL-18的活化[[[] Nebel Christopher,Aslanidis Alexander,Rashid Khalid et al. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells.[J] .Biochem. Biophys. Res. Commun., 2017, 484: 681-686.]]。综上表明炎症因子与免疫应答是DR发生发展中的重要机制。
1.2氧化应激及多元醇通路与DR
正常情况下，进入电子传递链的氧分子后被分解为超氧化物，活性氧自由基(Ros)和其余氧被用于代谢过程，其中活性氧自由基(Ros) 是体内氧代谢的副产 ，物。细胞内的Ros主要来源于线粒体电子呼吸链和胞质辅酶烟酰胺腺嘌呤二核苷酸磷酸(Nicotinamide adenine dinucleotide phosphate, NADPH）的催化，生理剂量的Ros参与细胞生理活动的调节。在高糖情况下，Ros和活性氮自由基(RNs)产量增加，导致氧化系统和抗氧化系统失去平衡，引起细胞内的生物大分子受损,胞膜脂质出现过氧化,DNA氧化受损,最终导致细胞凋亡，激活氧化应激，导致DR发生。随后氧化应激与DR的另一机制多元醇通路相互促进[[[] Kowluru Renu A,Kowluru Anjan,Mishra Manish et al. Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy.[J] .Prog Retin Eye Res, 2015, 48: 40-61.]]。多元醇通路是细胞内的代谢过程，参与其过程的包括葡萄糖、醛糖还原酶及山梨醇脱氢酶、山梨醇等相关因素。在高血糖下，多元醇通路被激活，山梨醇产生。山梨醇在细胞内积累，引起细胞的损伤，促进DR的进展[[[] Lorenzi Mara,The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient.[J] .Exp Diabetes Res, 2007, 2007: 61038.]]。另外多元醇通路的激活，导致谷胱甘肽减少，进一步增加了氧化应激[[[] Xue J , Ray R , Singer D , et al. The Receptor for Advanced Glycation End Products (RAGE) Specifically Recognizes Methylglyoxal-Derived AGEs[J]. Biochemistry, 2014, 53(20):3327-3335.]]。综上证明在DR的发生发展中，多元醇通路的激活和氧化应激相互影响，共同推进DR发展。
1.3糖基化终末产物及生长因子与DR
晚期糖基化终末产物(Advanced Glycation End Products,AGEs),AGEs属于稳定的共价化合物，和蛋白质，脂肪等有关。近年来,越来越多的研究表明,AGEs在DR的发生发展中起着重要的作用[[[] Kandarakis Stylianos A,Piperi Christina,Topouzis Fotis et al. Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases.[J] .Prog Retin Eye Res, 2014, 42: 85-102.]]。在糖尿病患者中，长期高血糖导致AGEs的累积加快，AGEs可与细胞表面的受体结合，激活细胞内信号通路，导致促炎症细胞因子表达增加如TNF、IL-1等，并促进生长因子如肝细胞生长因子IGF-1（Hepatocyte growth factor，IGF-1）和血管内皮生长因子VEGF(Vascular endothelial growth factor,VEGF)等的表达[[[] Ma L，Zhou Z，ZhangD，et a1．Bmi-l regulates autoreactive CD4+T cell survival in immune Ihmmbocytopenia patients[J]．J Clin Immunol， 2012，32(3)：505-513．]]。
期刊文章分类查询,尽在期刊图书馆实验证明AGEs可引起细胞内黏附因子水平升高，促使视网膜毛细血管内白细胞的黏附，导致BRB功能功能障碍[[[] Takahashi N , Saitoh T , Gotoh N , et al. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP[J]. BMC Immunology, 2017, 18(1):26.]]。研究证明认为IGF-1和VEGF与DR发生发展相关。IGF-1可破坏BRB，增加视网膜血管的通透性，并且在视网膜缺氧状态下，促进视网膜新生血管的形成[[[] Xuan Min,Li Huiyuan,Fu Rongfeng et al. Lack of association between NR3C1 polymorphism and glucocorticoid resistance in Chinese patients with immune thrombocytopenia.[J] .Platelets, 2014, 25: 125-8.]]。有研究表明, DR患者血清中VEGF的水平在病变发展过程中存在显著差异，它随着病变的加重而逐渐增加。这提示VEGF的与病情程度相关，在DR发生发展中起着重要作用[[[] 葛倩, 严国明, 季飞.2型糖尿病视网膜病变与血管内皮生长因子的关系[J].江苏医药, 2013, 39 (21) :2592-2593.]][[[] 罗君华.同型半胱氨酸、血管内皮生长因子及超敏C反应蛋白在2型糖尿病合并视网膜病变患者中的表达及意义[J].海南医学院学报, 2013, 19 (11) :1539-1541.]]。VEGF可以特异性地作用于血管内皮细胞,促进血管内皮细胞分裂，破坏原有内皮细胞结构, 使基底膜松动, 使内皮细胞不断增生，从而诱导视网膜新生血管生成[[[] 曹建峰, 庞东渤, 叶文婕.HIF-1α及VEGF在增生性糖尿病视网膜病变视网膜前膜中的表达[J].国际眼科杂志, 2013, 13 (5) :857-860.]]。从而影响DR发生发展。
1.4蛋白激酶C激活及自噬与DR
自噬是细胞进化中保守的溶酶体降解途径，它与细胞死亡和存活存在联系。DR相关因素与自噬过程密切相关，如内质网（Endoplasmic network，EN）应激，氧化应激、缺氧、细胞毒性和感染等[[[] Lin W.J, Kuang HY. Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells[J].Autophagy,2014,10(10): 1692-1701. ]]。有研究表明AMP活化蛋白激酶(Activated protein kinase，AMPK)激活自噬不论血糖高低，均可导致自噬对视网膜有害[[[] Emery M, Schorderet D F, Roduit R. Acute hypoglycemia induces retinal cell death in mouse[J]. PLoS One, 2011, 6(6):e21586. ]]AMPK-mTOR、Akt-mTOR信号通路，会引起DR大鼠细胞自噬[[[] 徐赵钕,章仕淼,刘玲玲.明目地黄丸对糖尿病视网膜病变大鼠细胞自噬及 Akt-mTOR 通路的影响[J].中国医药导报,2018,15(20):16-20．]]。p62 是反映自噬活性的标记蛋白之一，当自噬活性减弱、自噬功能缺陷时，p62 蛋白会在细胞质中不断累积过度表达，其含量间接反映自噬小体清除水平[[[] Moscat J,Diaz-Meco M T. p62 at the crossroads of autophagy, apoptosis, andcancer[J]. Cell, 2009, 137(6):1001-1004.]]。这些研究表明蛋白激酶在自噬的通路中起着重要的作用,自噬与DR的发生发展密不可分。
2.总结与展望
糖尿病视网膜病变是糖尿病最主要的并发症之一，目前虽然已经有较多研究阐释了DR的发病病机及各发病因素之间相互影响，相互促进，共同致病的机理。但是各因素间相关作用的具体机理并未完全阐释，其确切的发病机制目前尚不明确。临床诊疗和动物实验在DR的药物治疗上已取得一定的疗效，但是距离DR治愈还存在一定距离。所以进一步深入探究DR的发病机制，研究最佳治疗策略，将很大程度上防止DR发生进展,降低DR致盲率。
参考文献
[] Yau JW, Rogers SL, Kawasaki R. Global prevalence and major risk factors of diabetic retinopathy[J].Diabetes Care ,2012,35(3):556-564.
[] 崔颖.广东省东莞市糖尿病视网膜病变流行病学研究[D].广州:南方医科大学,2013:2.
[] Ferris FL. III Results of 20 years of research on the treatment of diabetic retinopathy[J]. Prev Med,1994, 23(5), 740-742.
[]Adamis Anthony P,Berman Adrienne J,Immunological mechanisms in the pathogenesis of diabetic retinopathy.[J] .Semin Immunopathol, 2008, 30: 65-84.
[] Huang Hu,Gandhi Jarel K,Zhong Xiufeng et al. TNFalpha is required for late BRB breakdown in diabetic retinopathy, and its inhibition prevents leukostasis and protects vessels and neurons from apoptosis.[J] .Invest. Ophthalmol. Vis. Sci., 2011, 52: 1336-44.
[] Shen Xi,Xie Bing,Cheng Yu et al. Effect of pigment epithelium derived factor on the expression of glutamine synthetase in early phase of experimental diabetic retinopathy.[J] .Ocul. Immunol. Inflamm., 2011, 19: 246-54.
[] Teunissen M B,Koomen C W,de Waal Malefyt R et al. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes.[J] .J. Invest. Dermatol., 1998, 111: 645-9.
[] Semeran Kornel,Paw?owski Przemys?aw,Lisowski ?ukasz et al. Plasma levels of IL-17, VEGF, and adrenomedullin and S-cone dysfunction of the retina in children and adolescents without signs of retinopathy and with varied duration of diabetes.[J] .Mediators Inflamm., 2013, 2013: 274726.
[] 卞征. 白介素和糖尿病视网膜病变的关系[D].南京医科大学,2017.
[] Chen Mei,Xu Heping,Parainflammation, chronic inflammation, and age-related macular degeneration.[J] .J. Leukoc. Biol., 2015, 98: 713-25.
[] Nebel Christopher,Aslanidis Alexander,Rashid Khalid et al. Activated microglia trigger inflammasome activation and lysosomal destabilization in human RPE cells.[J] .Biochem. Biophys. Res. Commun., 2017, 484: 681-686.
[] Kowluru Renu A,Kowluru Anjan,Mishra Manish et al. Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy.[J] .Prog Retin Eye Res, 2015, 48: 40-61.
[] Lorenzi Mara,The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient.[J] .Exp Diabetes Res, 2007, 2007: 61038.
[] Xue J , Ray R , Singer D , et al. The Receptor for Advanced Glycation End Products (RAGE) Specifically Recognizes Methylglyoxal-Derived AGEs[J]. Biochemistry, 2014, 53(20):3327-3335.
[] Kandarakis Stylianos A,Piperi Christina,Topouzis Fotis et al. Emerging role of advanced glycation-end products (AGEs) in the pathobiology of eye diseases.[J] .Prog Retin Eye Res, 2014, 42: 85-102.
[] Ma L，Zhou Z，ZhangD，et a1．Bmi-l regulates autoreactive CD4+T cell survival in immune Ihmmbocytopenia patients[J]．J Clin Immunol， 2012，32(3)：505-513．
[] Takahashi N , Saitoh T , Gotoh N , et al. The cytokine polymorphisms affecting Th1/Th2 increase the susceptibility to, and severity of, chronic ITP[J]. BMC Immunology, 2017, 18(1):26.
[] Xuan Min,Li Huiyuan,Fu Rongfeng et al. Lack of association between NR3C1 polymorphism and glucocorticoid resistance in Chinese patients with immune thrombocytopenia.[J] .Platelets, 2014, 25: 125-8.
[] 葛倩, 严国明, 季飞.2型糖尿病视网膜病变与血管内皮生长因子的关系[J].江苏医药, 2013, 39 (21) :2592-2593.
[] 罗君华.同型半胱氨酸、血管内皮生长因子及超敏C反应蛋白在2型糖尿病合并视网膜病变患者中的表达及意义[J].海南医学院学报, 2013, 19 (11) :1539-1541.
[] 曹建峰, 庞东渤, 叶文婕.HIF-1α及VEGF在增生性糖尿病视网膜病变视网膜前膜中的表达[J].国际眼科杂志, 2013, 13 (5) :857-860.
[] Lin W.J, Kuang HY. Oxidative stress induces autophagy in response to multiple noxious stimuli in retinal ganglion cells[J].Autophagy,2014,10(10): 1692-1701.
[] Emery M, Schorderet D F, Roduit R. Acute hypoglycemia induces retinal cell death in mouse[J]. PLoS One, 2011, 6(6):e21586.
[] 徐赵钕,章仕淼,刘玲玲.明目地黄丸对糖尿病视网膜病变大鼠细胞自噬及 Akt-mTOR 通路的影响[J].中国医药导报,2018,15(20):16-20．
[] Moscat J,Diaz-Meco M T. p62 at the crossroads of autophagy, apoptosis, andcancer[J]. Cell, 2009, 137(6):1001-1004.
论文作者:黎琳娟,游英帆,宿晓娟,蒋怡,陈家利,谭蓉
论文发表刊物:《医师在线》2019年6月12期
论文发表时间:2019/9/23
标签：视网膜论文; 糖尿病论文; 内皮论文; 细胞论文; 血管论文; 炎症论文; 机制论文; 《医师在线》2019年6月12期论文;