New advances on the mechanism of age-related macular degeneration

doi:10.3877/cma.j.issn.2095-2007.2024.04.009

Abstract

Abstract:

Age-related macular degeneration（AMD）is one of the leading causes of blindness among old adults worldwide.There are two types of advanced AMD：neovascular AMD and map atrophy，both of which are associated with severe progressive visual impairment.Major risk factors for AMD include smoking，nutritional factors，cardiovascular disease，and genetics，etc.It has been domonstrated that the incidence of AMD has an increasing trend，especially for the young population.It is necessary for accurate diagnosis of AMD to combinate of slit-lamp microscopy with auxiliary examinations，including retinography，fundus fluorescein angiography，and optical coherence tomography.Treatment for neovascular AMD includes intraocular injection of anti-vascular endothelial growth factor drugs，combination with other therapies，including inhibition of other angiogenic factors， regenerative therapy， local therapy and dietary supplementation of antioxidants.However，the current treatment effect of the disease is not good enough.Therefore，it is of great value to explore its pathogenesis from the aspects of lipid deposition，inflammation and complement system.

Key words: Age-related macular degeneration, Lipid deposition, Inflammation, Complement system

Yang Zhang, Shasha Luo, Wenjun Zou. New advances on the mechanism of age-related macular degeneration[J]. Chinese Journal of Ophthalmologic Medicine(Electronic Edition), 2024, 14(04): 240-246.

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References 68

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相关因素	机制及作用	文献
脂质	脂质是BrM的重要组成部分。BrM是AMD的标志性特征。脂酶C、血浆胆固醇酯转移蛋白、ATP结合盒转运体A1及载脂蛋白E等多个脂质相关基因的变异与AMD有关。	［4-5］
小胶质细胞和中性粒细胞	小胶质细胞在视网膜的稳态和变性中发挥着重要作用。RPE源性因子激活小胶质细胞中的Akt2。Akt2可增加小胶质细胞的促炎转变和中性粒细胞的活化，这有助于向组织内迁移。	［4，11-12］
脉络膜肥大细胞	血小板反应蛋白-1在调节脉络膜肥大细胞平衡和激活AMD发病机制中发挥着重要作用。CFH、HTRA1及血小板反应蛋白-1活性调节之间可能有相互作用关系，继而促进血管生成和炎症反应。	［15］
铁死亡	铁的积累和细胞内抗氧化防御系统效率的降低使老化的视网膜易于发生氧化应激诱导的细胞死亡。	［16］
遗传和环境因素	HTRA1基因所在的染色体10q26区域是与AMD关联性最强的基因位点之一。HTRA1作用于细胞外基质蛋白，包括BrM。BrM的逐渐降解会使血管更容易从脉络膜通过BrM生长到神经视网膜，从而增加其发展为新生血管性AMD的风险。	［22-24］
先天免疫	AMD中免疫激活的特征包括细胞外沉积物的形成、局部免疫激活、视网膜下及脉络膜小胶质细胞或巨噬细胞的招募。	［5］
补体系统	补体介导导致AMD的分子过程可能是由全身性补体蛋白以及局部合成补体蛋白的组合。CFH基因中的一个常见多态性（Y402H）与AMD患病风险的增加密切相关。这种变异可能会改变CFH的功能，导致补体途径过度激活，进而引发炎症和组织损伤，这是AMD的标志。	［33-35］
上皮-间质转化	RPE的上皮-间质转化在nAMD视网膜下纤维化的发病机制中发挥着关键作用。上皮-间质转化是nAMD视网膜下纤维化形成的关键过程。在nAMD中，上皮-间质转化会损害RPE结构的完整性并促进感光细胞变性。	［46］
血管生成素Ang-1和Ang-2	Tie-2在内皮细胞上表达，并且Ang-1和Ang-2都是参与血管生成和血管通透性的生长因子。当Ang-2上调时，可能发生病理性新血管形成和血管通透性增加。	［49］
整合素	与整联蛋白结合的天冬氨酰-甘氨酰-天冬氨酸在眼组织中表达，且能参与炎症、血管渗漏、血管生成及纤维化过程。	［51，53］
线粒体功能障碍	外层视网膜的高代谢活动会使RPE和（或）感光细胞易受线粒体氧化损伤的影响。这些变化可能导致ATP生成减少、氧化应激增加及细胞死亡途径激活，从而导致RPE细胞死亡，感光细胞变性，AMD进展。以线粒体融合异常增加和线粒体周转减少为特征的高融合状态已被确定为RPE衰老的驱动因素。	［55-57］
自噬	RPE细胞中脂褐素双酯的积累会破坏自噬的正常功能，导致胆固醇的积累和酸性鞘磷脂酶的激活，从而阻碍自噬体的移动。自噬通量的减少会导致脂褐质在溶酶体中积累。而脂褐质是一种光诱导的ROS来源，被认为是RPE细胞中蓝光相关损伤的启动因子。	［15，64-65］
氧化应激	视网膜因其外层-RPE复合物耗氧量高、累积辐照水平高、RPE中光敏剂丰富及感光体外节膜富含多不饱和脂肪酸等特殊的解剖和代谢特征，容易被氧化，生成ROS，引发细胞毒性连锁反应。	［66］
新生血管	脂蛋白碎屑的氧化变化可形成有利于血管生长的促血管生成信号。在nAMD中，氧化脂蛋白碎片的一个主要成分是7-酮胆固醇，其可诱导血管生成。VEGF可促进脉络膜内皮细胞的活化和迁移。靠近RPE细胞的脉络膜内皮细胞可能通过RPE细胞分泌的VEGF进一步激活。	［2］

相关因素	机制及作用	文献
脂质	脂质是BrM的重要组成部分。BrM是AMD的标志性特征。脂酶C、血浆胆固醇酯转移蛋白、ATP结合盒转运体A1及载脂蛋白E等多个脂质相关基因的变异与AMD有关。	［4-5］
小胶质细胞和中性粒细胞	小胶质细胞在视网膜的稳态和变性中发挥着重要作用。RPE源性因子激活小胶质细胞中的Akt2。Akt2可增加小胶质细胞的促炎转变和中性粒细胞的活化，这有助于向组织内迁移。	［4，11-12］
脉络膜肥大细胞	血小板反应蛋白-1在调节脉络膜肥大细胞平衡和激活AMD发病机制中发挥着重要作用。CFH、HTRA1及血小板反应蛋白-1活性调节之间可能有相互作用关系，继而促进血管生成和炎症反应。	［15］
铁死亡	铁的积累和细胞内抗氧化防御系统效率的降低使老化的视网膜易于发生氧化应激诱导的细胞死亡。	［16］
遗传和环境因素	HTRA1基因所在的染色体10q26区域是与AMD关联性最强的基因位点之一。HTRA1作用于细胞外基质蛋白，包括BrM。BrM的逐渐降解会使血管更容易从脉络膜通过BrM生长到神经视网膜，从而增加其发展为新生血管性AMD的风险。	［22-24］
先天免疫	AMD中免疫激活的特征包括细胞外沉积物的形成、局部免疫激活、视网膜下及脉络膜小胶质细胞或巨噬细胞的招募。	［5］
补体系统	补体介导导致AMD的分子过程可能是由全身性补体蛋白以及局部合成补体蛋白的组合。CFH基因中的一个常见多态性（Y402H）与AMD患病风险的增加密切相关。这种变异可能会改变CFH的功能，导致补体途径过度激活，进而引发炎症和组织损伤，这是AMD的标志。	［33-35］
上皮-间质转化	RPE的上皮-间质转化在nAMD视网膜下纤维化的发病机制中发挥着关键作用。上皮-间质转化是nAMD视网膜下纤维化形成的关键过程。在nAMD中，上皮-间质转化会损害RPE结构的完整性并促进感光细胞变性。	［46］
血管生成素Ang-1和Ang-2	Tie-2在内皮细胞上表达，并且Ang-1和Ang-2都是参与血管生成和血管通透性的生长因子。当Ang-2上调时，可能发生病理性新血管形成和血管通透性增加。	［49］
整合素	与整联蛋白结合的天冬氨酰-甘氨酰-天冬氨酸在眼组织中表达，且能参与炎症、血管渗漏、血管生成及纤维化过程。	［51，53］
线粒体功能障碍	外层视网膜的高代谢活动会使RPE和（或）感光细胞易受线粒体氧化损伤的影响。这些变化可能导致ATP生成减少、氧化应激增加及细胞死亡途径激活，从而导致RPE细胞死亡，感光细胞变性，AMD进展。以线粒体融合异常增加和线粒体周转减少为特征的高融合状态已被确定为RPE衰老的驱动因素。	［55-57］
自噬	RPE细胞中脂褐素双酯的积累会破坏自噬的正常功能，导致胆固醇的积累和酸性鞘磷脂酶的激活，从而阻碍自噬体的移动。自噬通量的减少会导致脂褐质在溶酶体中积累。而脂褐质是一种光诱导的ROS来源，被认为是RPE细胞中蓝光相关损伤的启动因子。	［15，64-65］
氧化应激	视网膜因其外层-RPE复合物耗氧量高、累积辐照水平高、RPE中光敏剂丰富及感光体外节膜富含多不饱和脂肪酸等特殊的解剖和代谢特征，容易被氧化，生成ROS，引发细胞毒性连锁反应。	［66］
新生血管	脂蛋白碎屑的氧化变化可形成有利于血管生长的促血管生成信号。在nAMD中，氧化脂蛋白碎片的一个主要成分是7-酮胆固醇，其可诱导血管生成。VEGF可促进脉络膜内皮细胞的活化和迁移。靠近RPE细胞的脉络膜内皮细胞可能通过RPE细胞分泌的VEGF进一步激活。	［2］

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