1. 引言
年龄相关性黄斑变性(AMD)是一种迟发性、进行性变性疾病,主要表现为黄斑区非感染性损伤,患者多见于50岁以上,是发达国家老年人主要的致盲眼病之一 [1] 。随着我国人口老龄化及中国人生活饮食习惯的变化,老年性黄斑变性患者也日趋增多 [2] 。干性AMD开始表现进行性的视网膜色素上皮(RPE)和光感受器变性及玻璃膜疣形成,晚期出现黄斑区地图样萎缩 [3] ;脉络膜新生血管生成是湿性AMD的主要特征。根据调查发现:AMD患者中干性占85%~90%,其中地图样萎缩患者占10%~20% [4] 。目前对于干性AMD仍无彻底的治疗方法,本文就干性AMD的发病机制及危险因素进行综述,从而早期干预干性AMD提供新的思路和方法。
2. 遗传因素
干性老年黄斑病变发病呈现出的家族聚集、分离现象及双生子研究均提示遗传因素起重要作用,大量家系研究显示,干性AMD遗传率可达71% [5] [6] ;且有研究表明:与非AMD患者的一级亲属相比,AMD患者的一级亲属患AMD的危险度高达2.4倍,且发病年龄更年轻 [7] 。
基因突变已被证实参与了干性AMD的发病,且可能为多基因变异,包括易感基因和抑制基因共同作用的结果。Fisher等 [8] 采用基因组扫描整合分析技术将世界上6个已发表的研究结果进行归纳,证实与AMD易感性关系最密切的基因位点为染色体10q26、1q、2q、3q、和16。补体因子H(CFH)位于染色体1q上,CFH基因1277位的碱基胸腺嘧啶T突变为胞嘧啶C,导致其密码子402位的组氨酸替代为酪氨酸后形成变异体Y402H,它是全基因组关联分析技术确定的第一个与AMD有显著相关性的等位基因 [9] ,CFH是补体替代激活途径的重要活性调节因子。研究显示:因子B(BF)和补体成分2(C2)基因编码2种补体调节蛋白,其基因的多态性具有1个风险性单元型和2种保护性单元型基因,前者可提高干性AMD风险(OR, 1.32),后者可分别降低干性AMD风险(OR,0.45和0.36) [10] 。Allikmets等 [11] 发现ABCA4基因与干性AMD相关,在出现临床症状的早期发生改变。Zhou等 [12] 发现TLR3基因多态性具有保护作用,能减少干性AMD发生风险,可导致TLR3与双链RNA的结合能力下降50%,从而减少RPE细胞的凋亡,降低干性AMD的发病风险。
3. 衰老
视网膜色素上皮(RPE)细胞的正常功能对于防止干性AMD发病有非常重要的作用,RPE细胞损伤是AMD病理改变的始动环节 [13] 。正常RPE在视网膜光感受器的营养维持、合成生长因子及调整局部结构和视觉周期等方面起到了重要作用。但随着年龄增长,黄斑区RPE细胞数量减少、功能减退、细胞内脂褐质逐渐积聚及染色体端粒变短。RPE细胞功能减退主要变现在以下方面: ① 色素上皮源性因子(PEDF)是一种内源性非抑制性丝氨酸蛋白酶抑制剂,在维持视网膜正常的生理功能方面具有重要作用 [14] [15] 。RPE细胞是眼内产生PEDF的主要细胞,在胎儿及青年人的RPE细胞中PEDF高表达,但老年人RPE细胞中PEDF表达下调。 ② 随着年龄的增长,RPE细胞吞噬和代谢作用减退。RPE细胞内黑色素颗粒不仅对RPE细胞及视网膜神经细胞都有重要保护作用,而且还能够绑定视网膜内的毒性物质 [16] 。但随着年龄的增长,RPE细胞内黑色素不断减少。
干性AMD会出现脂褐素过度积累 [17] 。脂褐素是由光感受器外节膜盘被RPE细胞吞噬后仅部分被酶消化,残余的部分积累形成 [18] 。RPE细胞内脂褐素的含量的多少则反应了细胞老化的程度。张娟美等 [19] 利用体外培养的老年牛RPE细胞吞噬负荷量的感光细胞外节段后,发现RPE细胞明显凋亡,并且细胞凋亡的数量随剂量的增加和时间的延长而增多。脂褐素含有蛋白、脂性物质,及碳水化合物,其主要成分为N视黄基N视黄乙醇胺(A2E)。
A2E是亲脂性阳离子,对RPE细胞功能的损伤主要体现在4各方面: ① 降低RPE细胞的抗氧化能力。有研究表明体外培养的RPE细胞吞噬脂褐素颗粒后能够降低60%抗氧化物歧化酶和过氧化氢酶的抗氧化能力 [20] 。 ② A2E可诱导RPE细胞损伤及发生凋亡。Sparrow等 [21] 在人RPE细胞的培养基中加入不同浓度的A2E溶液,然后用蓝光(480 nm)照射15 s到60 s,发现凋亡细胞的数量呈现光照时间和A2E浓度依赖方式。 ③ A2E能抑制溶酶体对代谢物质的降解,增加视网膜光化学毒性,降低RPE细胞的吞噬能力。 ④ A2E能够破坏RPE细胞膜结构。A2E是由两分子视黄醛和一份子氨基乙醇合成,分子结构具有2个疏水的尾部和1个亲水的头部,可以像去污剂一样破坏生物膜的完整性 [22] 。
4. 氧化应激
氧化应激是干性AMD发病的重要病理机制。视网膜对氧的消耗量远高于其它组织,且RPE层位于视网膜和脉络膜毛细血管之间,处于极高的氧分压环境中;在可见光下的条件下,RPE细胞吞噬并消化富含多不饱和脂肪酸的光感受器细胞外节,而不饱和脂肪酸在高氧的环境中很容易被氧化,并且引起一连串氧化反应,从而产生大量活性氧(ROS)。
研究发现:在干性AMD的病程中,增加氧化应激损伤的因素能够加重病情,而降低氧化应激损伤的因素能够延缓病情 [23] 。陈丽等 [24] 研究发现,H2O2可以促进基质金属蛋白酶的表达,抑制基质金属蛋白酶抑制剂的表达,从而导致AMD时Bruch膜增厚、玻璃膜疣的形成。在氧化应激状态下,线粒体易发生功能障碍,诱导并促进RPE细胞凋亡。赵颖等 [25] 将体外的人RPE细胞经过氧化氢处理后,发现停留在静止期和合成前期的细胞增多,随过氧化氢作用时间的延长,生长停滞越发明显;在72小时达到高峰;线粒体膜电位降低,随时间延长逐渐降低;凋亡途径中的核心上游因子Cappse-9增加,随时间延长而增加,在24小时达到高峰,72小时略有回落,但仍明显高于正常。提示过氧化氢氧化损伤导致的人RPE细胞生长停滞,细胞衰老的机制可能与线粒体膜电位降低导致的线粒体代谢障碍和Cappse-9介导的线粒体凋亡途径有关。
4.1. 光照损伤
光照损伤是干性AMD的致病因素之一。人眼接受的光照包括紫外光(100~400 nm)和可见光(400~750 nm)。波长小于340 nm的紫外光虽然为高能光波,但由于角膜和晶状体的有效滤过,到达视网膜的不到1%,不易对视网膜造成损伤。而波长在400 nm左右的近蓝光光线因为能量高,且视锥细胞对蓝光最敏感,它的最大吸收光谱是440 nm,因此可以造成较大的视网膜损伤。光照损伤导致AMD是通过造成RPE细胞功能障碍甚至凋亡而最终导致AMD,且损伤程度与光暴露能量成正比 [26] 。1966年Noell等 [27] 用可见光持续照射自由活动的大鼠,发现大鼠光感受器细胞出现明显的选择性凋亡。Boulton [28] 研究发现蓝光可诱导黑色素小体发生光化学反应从而产生ROS。Davies等 [29] 的研究显示:将体外培养的人RPE细胞暴露于390~550 nm波长的可见光下(实验组),而对照组细胞一直保存于黑暗中,6 h后发现实验组细胞线粒体活性相比对照组有所下降。Sparrow等 [30] 发现含有脂褐素的RPE细胞在蓝光照射后可以直接造成DNA损伤,且此损伤与光照持续时间成正比。由此可见,光线尤其是蓝光导致RPE细胞早期的损伤,是干性AMD的重要危险因素。
4.2. 炎症与免疫
干性AMD的临床特点之一为玻璃膜疣的形成,主要有补体成分,树突状细胞突、C反应蛋白、补体调节蛋白、糖基化终末产物、视网膜色素上皮脱落的细胞碎屑、免疫球蛋白、脂褐素、免疫复合物、玻璃体结合蛋白及纤维蛋白等 [31] 。有研究显示C反应蛋白的升高与AMD成正相关 [32] ,提示干性AMD发病过程中有免疫炎症反应的参与。在免疫系统的光毒性反应中,巨噬细胞因受脉络膜血管中树突状细胞的细胞碎片吸引而聚集,引起局部自身免疫反应和慢性炎症 [33] [34] 。但是,抗氧化剂能在局部保护光感受器和RPE不受光毒性损伤 [35] 。由此可见,AMD的慢性炎症与光毒性反应之间有相互联系,其一,光感受器外节的不饱和脂肪酸被光照射后会释放出花生四烯酸,形成前列腺素及白三烯等炎症因子,从而引起巨噬细胞聚集;其二,光毒性反应引起光感受器和RPE细胞凋亡,凋亡小体会引起胶质细胞聚集,并且它们是形成玻璃膜疣的底物,又会激活树突状细胞,吸引巨噬细胞聚集,在视网膜内引起炎症反应的恶性循环。但丛生蛋白也是玻璃膜疣的主要蛋白成分之一,RPE细胞是分泌丛生蛋白的主要细胞,研究发现在异常炎症相关因子聚集的情况下,丛生蛋白能与炎症因子相结合,阻止蛋白的聚集反应,抑制C5b-9膜攻击复合物的形成,从而抑制炎症反应 [36] [37] 。
4.3. 吸烟
有研究表明,与不吸烟者相比,吸烟者发生干性AMD的相对危险度是2.54,且影响其发展 [38] [39] 。Fujihara等 [40] 发现在动物模型中,长期慢性吸烟容易造成RPE细胞膜折叠,细胞内出现空泡结构、视网膜中Bruch膜增厚等超微结构的改变,这些改变和早期AMD中RPE细胞凋亡的特征性病理改变相一致。
Evans [41] 发现吸烟能增加患AMD的风险,但饮食中摄入大量抗氧化剂可以降低AMD患病风险,提示吸烟会通过氧化应激的方式损伤黄斑区的视网膜。香烟中引起氧化应激损伤的物质主要有金属镉、丙烯醛及氢醌。并且这些物质已经被证明参与了RPE细胞损伤的体外或体内模型 [42] [43] 。吸烟者血浆中的烟碱和可铁宁还会激活视网膜磷脂酶A2,从而生成前列腺素及白三烯前体–花生四烯酸等炎性介质。加重视网膜部的慢性炎症,促进AMD的发展。吸烟也会导致脉络膜血流动力学发生改变, ① 香烟可激活α-肾上腺素能受体,引起脉络膜局部血流量减少; ② 慢性烟雾改变了血液凝固动力学和纤维蛋白结构,二者相互作用有助于局部血栓形成 [44] 。
5. 局部血流灌注
随着年龄的增长,组织学检查见眼部动脉硬化,血管管壁增厚,脉络膜毛细血管区域减少,毛细血管之间的结缔组织变宽,尤其显著的改变是黄斑光反射区下的脉络膜毛细血管床的减少提示AMD可能是因缺血导致。有研究显示AMD早期患者血脂异常升高,血液粘稠 [45] [46] 。血流参数中阻力指数(RI)和搏动指数(PI)反应的是血管内血流阻力的大小,收缩期峰值流速(PSV)能够反应血管充盈程度和血流供应强度,而舒张末期最大血流速度值(EDV)反应的是远端组织的血液灌注状态,RI、PI越大,说明血管内血流阻力越大,PSV越大,说明血管内血流供应充足,EDV明显下降,提示远端组织的血供不足 [47] 。研究显示,AMD患者与健康人相比,视网膜中央动脉(CRA)和睫状后动脉(PCA)血流动力学变化具有显著性差异(P < 0.05),表现为PSV降低、EDA变缓、RI、PI值增加(P < 0.05) [48] 。并且有调查显示:糖尿病患者AMD的发病率是无糖尿病病史的2.5倍,糖尿病患者的持续高血糖状态使得微循环功能较差,在视网膜部表现为血流量减少及速度减低,容易导致黄斑区部分微血管阻塞,造成神经节细胞凋亡,最终导致中心视力的降低 [49] 。
6. 总结
我国干性AMD患者日益增多,但仍无有效治疗手段。因此,研究其发病的危险因素对预防及治疗干性AMD有重要意义。目前,RPE细胞损伤被认为是其始动环节,而光照损伤、炎症反应、脂褐素积累、玻璃膜疣的形成、氧化损伤以及局部血流关注改变均会引起RPE细胞损伤,促进干性AMD形成。但对其相关损伤机制还需要进行更深入的研究,为治疗干性AMD提供更早期的干预和有效的治疗。
基金项目
江西省自然基金(2015BAB205026)、江西省社会发展领域基金(2015BBG70171),南昌大学第二附属医院院级课题(2016YNZJ12001)。
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