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湿性年龄相关性黄斑变性视网膜下纤维化的研究进展

Research progress of subretinal fibrosis in wet age-related macular degeneration

来源期刊： 眼科学报 | 2023年9月 第38卷 第9期： 633-640 发布时间： 收稿时间：2024/1/17 17:25:10 阅读量：2376
作者：
刘诗晗,
周希瑗,
关键词：
视网膜下纤维化湿龄相关性黄斑变性黄斑区新生血管基线特征综述
subretinal fibrosis wge-related macular degeneration macular neovascularization baseline features review
DOI：
10.12419/2307310002
年龄相关性黄斑变性(age-related macular degeneration,AMD)是一种发生在黄斑区的退行性变，其中湿性年龄相关性黄斑变性(wet age-related macular degeneration,wAMD)以黄斑区新生血管为主要病理特征，是导致老年人视力受损甚至失明的重要原因，视网膜下纤维化是wAMD最常见的自然后遗症，可导致光感受器、视网膜色素上皮(retinal pigment epithelial,RPE)和脉络膜毛细血管受损，导致不可逆转的中心视力丧失。多种基线特征被发现是视网膜下纤维化的危险因素，可用于预测早期视网膜下纤维化的发生。迄今为止，还没有有效的抗纤维化治疗方法，抗血管内皮生长因子(anti-vascular endothelia growth factor, anti-VEGF)治疗是wAMD的一线治疗方案，该治疗方法不能改善视网膜下纤维化，但及时启动治疗可能有助于预防或延缓纤维化的进展，目前多种靶向分子药物正被研发用于抗纤维化的治疗。该文综述了wAMD视网膜下纤维化的临床表现及意义、预测纤维化形成的基线特征、基本发病机制及潜在的抗纤维化治疗方法，旨在为临床诊治工作提供参考。
Age-related macular degeneration (AMD) is a degenerative disease of the macular, and wet age-related macular degeneration(wAMD) is mainly characterized by macular neovascularization, which is an important reason of visual impairment or even blindness in the elderly. Subretinal fibrosis is the most common natural sequelae of wAMD, which can lead to irreversible central vision loss by damaging photoreceptors, RPE, and choroidal capillaries. Multiple baseline features have been identified as the risk factors for subretinal fibrosis, which can be used to predict the early subretinal fibrosis. Heretofore, no anti fibrotic treatment method is effective. Anti vascular endothelial growth factor (anti VEGF) treatment is the first-line treatment for wAMD. This therapy cannot improve subretinal fibrosis, but timely initiation of treatment may help prevent or delay the progression of fibrosis. Currently, multiple targeted molecular drugs are being developed for anti fibrotic treatment. This article reviews the clinical manifestations and significance of subretinal fibrosis in wet age-related macular degeneration, baseline features for predicting the formation of fibrosis, basic pathogenesis, and potential anti-fibrosis treatment methods,aiming to provide reference for clinical diagnosis and treatment.
年龄相关性黄斑变性(age-related macular degeneration,AMD)，是一种发生在黄斑区的退行性病变，也是全球5 0岁以上人群失明的主要原因之一[1]。据估计，到2040年，全世界将有约2.88亿人患有AMD[2]，根据2019年美国眼科学会的临床指南[3]，晚期AMD可分为两种不同的类型：地图样萎缩型和新生血管型AMD(neovascular age-related macular degeneration,nAMD)，新生血管型AMD又称湿性AMD(wet age-related macular degeneration,wAMD),通过破坏Bruch膜，形成黄斑区新生血管(macular neovascularization,MNV)，同时可能伴有视网膜硬性渗出、视网膜下出血、浆液性视网膜脱离、瘢痕等。
视网膜下纤维化是MNV最常见的后遗症，可导致视网膜下瘢痕形成，光感受器、视网膜色素上皮(retinal pigment epithelial,RPE)和脉络膜毛细血管发生永久性的损坏，造成无法挽回的中心视力丧失[4]。尽管抗血管内皮生长因子(anti-vascular endothelia growth factor,anti-VEGF)治疗已成为wAMD患者的一线治疗措施，使大部分患者视力获益，但研究表明[5]，在10年的观察期内，尽管进行了持续的抗VEGF治疗，约1/4的nAMD患者仍出现了严重的视力丧失(即损失超过15个ETDRS字母)。这种现象通常归因于anti-VEGF治疗后近半数nAMD患者出现了视网膜下纤维化。然而，人们对视网膜下纤维化的发病机制及影响因素知之甚少，到目前为止，还没有一种治疗方式可以有效地防止过度的视网膜下纤维化。本综述将从wAMD视网膜下纤维化的临床表现及意义、预测瘢痕形成的基线特征、发病机制、抗纤维化的治疗4个方面进行阐述。

1 临床表现及意义

临床上，视网膜下纤维化可通过眼底照相、荧光素血管造影、频域光学相干断层扫描(spectral domain optical coherence tomography,SD-OCT)和光学相干断层扫描血管造影(optical coherence tomography angiography, OCT-A)等多模式成像进行评估，并分为纤维化瘢痕和非纤维化瘢痕。纤维化瘢痕形状清晰，表现为明显隆起的白色或黄色纤维样组织，在检眼镜及眼底彩照上为实心状结构；非纤维化瘢痕通常是平坦、小、界限清晰的色素沉着区，并伴有不同程度的中央色素沉着减退。在荧光素血管造影中表现为病灶染色或下方脉络膜荧光阻断引起的强荧光，如果纤维化瘢痕内部存在活动性脉络膜新生血管(choroidal neovascularization,CNV)，则显示渗漏[6-7]。在OCT上，纤维化通常表现为致密的视网膜下高反射物质(subretinal hyper-reflective material,SHRM)。然而，在SD-OCT上，由于反射率相似，SHRM与RPE及无纤维血管的CNV有时难以鉴别。偏振敏感光学相干层析成像(polarization-sensitive optical coherence tomography,PS-OCT)是SD-OCT的一种功能扩展，Roberts等[8]的研究表明，可以根据PS-OCT的双折射和去极化特性鉴别纤维化和RPE及无纤维血管的CNV。首先PS-OCT提供基于去极化的自动RPE分割；其次视网膜下纤维化在PS-OCT上可以被识别为“柱状”双折射结构，这种图案源于纤维性瘢痕内胶原纤维的结构排列，而除纤维组织外的视网膜下高反射物质(如脂质、新生血管组织、血液)则不表现出这种模式[9]。
尽管上述成像技术提供了视网膜下纤维化周围视网膜结构改变的细节，但它们并没有提供纤维化瘢痕本身发生的结构变化。作为一种深度分辨率成像技术，OCTA能够显示纤维化瘢痕内的血管网络以及外层视网膜和脉络膜血管的侧支结构变化[10]。根据Souied等[11]报道，在OCTA上可检测到纤维化瘢痕内部主要有以下三种新生血管网模式：“修剪的血管树”“缠结的毛细血管网”和“血管袢”。此外，OCTA还发现在纤维化瘢痕病变的脉络膜毛细血管层可以观察到两种暗区，即血流空洞和暗晕病变。在与纤维化瘢痕相对应的脉络膜血管层的分割区中，血流空洞病变具有弥漫性信号缺乏。第二种类型的暗区，即暗晕，在脉络膜毛细血管区表现为围绕着新生血管网的一个暗环。在anti-VEGF治疗后的CNV复合物中，外周血管收缩，很少或没有血流，而中央“主干”血管变大且更加突出[12]。
由于视网膜下纤维化可造成色素上皮层及光感受器永久性的损伤，故纤维化是nAMD患者视力最重要的威胁之一。据Cheung等[13]报告称，未经治疗的nAMD患者发生视网膜下纤维化的比例在1年内从13.0%增加到37.8%。组织病理学研究表明，AMD患者眼的光感受器损伤的严重程度与视网膜下纤维化的大小成正比，基于此，Cheung等[13]提出视网膜下纤维化是能够预测最终视力的最重要的预测因子。然而，尽管进行了anti-VEGF治疗，nAMD患者的眼睛在2年内发生视网膜下纤维化的风险仍有45%[7]，而且出现中心凹下纤维化瘢痕的眼睛在anti-VEGF治疗后视力预后最差。Wu等[14]得出结论：视网膜下纤维化可作为预测wAMD对anti-VEGF治疗不完全应答的标志物。
因此，尽管视网膜下纤维化可通过限制渗出物而获益，但过度纤维化可导致视网膜下瘢痕形成，光感受器、RPE细胞和脉络膜血管发生不可逆转的破坏，从而使wAMD患者出现严重视力丧失。

2 视网膜下纤维化的影像学基线特征

明确wAMD患者发生视网膜下纤维化的危险因素，可以帮助预测患者的最终视力预后，制定更有个性化的治疗方案。目前，已有多项研究证实了wAMD患者发生视网膜下纤维化的各种危险因素，其中与纤维化相关的影像学特征包括2型CNV、视网膜内液(intraretinal fluid,IRF)、视网膜下高反射物质、出血、CNV病变大小和视网膜厚度，而视网膜下液(subretinal fluid,SRF)和色素上皮层脱离(pigment epithelium detachment,PED)可能具有保护作用。

2.1 MNV分型

为期2年的年龄相关性黄斑变性的对照治疗试验(Comparison of Age-related Macular Degeneration Treatments Trials,CATT)研究报道，2型MNV病变发生纤维化的风险是1型MNV的3倍，在其后随访5年的研究中也报告了类似的结果[15]。Romano等[16]进一步提出以经典型MNV为主的病变是发生视网膜下纤维化的独立危险因素。研究表明，与1型MNV相比，2型MNV更可能含有受损和分散的RPE，这些RPE可能经历了“上皮-间充质转化(epithelial-mesenchymal transition,EMT)”，导致细胞外基质(extracellular matrix,ECM)的过度沉积和重塑,因此更可能进展为纤维化。而2型MNV病变中有很大一部分是由1型MNV发展而来，因此，通过对wAMD的1型MNV阶段进行早期干预，可能减少视网膜下纤维化的发生。

2.2 IRF与SRF

近年来，有关视网膜积液位置的研究受到越来越多的关注。目前研究普遍认为IRF是纤维化的危险因素，而SRF则被认为对纤维化的发展具有保护作用。在Llorente-Gonzalez等[17]的研究中，SRF使wAMD发生纤维化和进展的风险减半，然而，IRF使纤维化发生和进展的风险增加了2倍，这可能与基线时IRF在2型MNV中出现的比例更高，而SRF在1型MNV中出现的比例更高有关。最新研究同样发现，基线时有SRF眼发生黄斑萎缩及视网膜下纤维化的风险均低于有IRF眼，表明视网膜下液可预防wAMD的黄斑萎缩和纤维化。这可能是由于SRF可通过其作为视网膜外节及其下的CNV之间的液体缓冲来保护光感受器，避免其受到直接浸润性损伤，或SRF本身可能含有神经保护物质[18]。

2.3 PED

在为期2年与5年的CATT研究中[7,15]，基线时存在PED与纤维化瘢痕的风险降低相关。 Teo等[19]进一步指出，基线时的PED对纤维化瘢痕的发生与进展具有保护作用。纤维化瘢痕的发生机制为RPE单层的破坏或RPE细胞-细胞接触的丧失可诱导上皮细胞向肌成纤维细胞的转分化，即EMT，而在PED中，视网膜内的液体被“困”在RPE层下，RPE细胞-细胞接触仍然完整，因此，PED可降低纤维化瘢痕的发生率。然而，在CATT数据的事后分析中，Finn等[20]发现基线时存在PED是wAMD患者在第5年时发生视网膜下纤维化瘢痕的风险因素。
Kim等[21]进一步探讨了老年性黄斑变性中多层PED(multilayered pigment epithelial detachment,m-PED)的形态学特征及预后意义，接受anti-VEGF持续治疗的慢性纤维血管PED表现出高度组织化、分层、高反射带的特征性梭形复合体，称为m-PED。m-PED内的隔室分为3层，第一层为新生血管组织、第二层为高反射带，第三层为高反射带与Bruch膜之间的脉络膜前裂。含有第 2 层的m-PED 具有较高的纤维化瘢痕形成风险，并且与较差的视觉预后相关，因此第 2 层的m-PED可能是纤维化瘢痕的早期前兆。
基线时PED与纤维化瘢痕之间的关系有待进一步探讨。在不同的研究中，造成PED纤维化瘢痕之间的不同关联的原因可能包括研究设计、治疗方案、注射次数和病变严重程度的差异。

2.4 SHRM

SHRM是纤维血管组织、出血、脂质、纤维蛋白和免疫细胞的混合物，在OCT上表现为高反射病灶。SHRM使神经感觉层视网膜和RPE之间的屏障增加，会干扰代谢和营养交换，并可能损伤被覆的光感受器，从而损害最终视力。Willoughby等[22]及Pokroy等[23]认为，抗VEGF治疗后SHRM厚度变化不明显者更早且更易出现视网膜瘢痕及萎缩，即SHRM的持续性与视网膜下纤维化的发展是一致的，基于此，Casalino等[25]在研究中又纳入SHRM的定量指标，得出SHRM的厚度和宽度是纤维化瘢痕的危险因素，但对非纤维化瘢痕没有影响。同时有研究表明，基线时SHRM的高反射率和清晰的边界可以被视为视网膜纤维化瘢痕演变的早期OCT生物标志物。这是因为OCT上清晰的SHRM边界代表纤维化组织或成熟的新生血管复合体。anti-VEGF治疗可以降低毛细血管内皮通透性，从而减少血管液体渗漏，当治疗持续一段时间，SHRM液体量相对减少时，纤维化成分可能会增加，anti-VEGF治疗可能诱导新生血管复合物成熟，其中高反射率随着时间的推移而增加，边界逐渐清晰。

2.5 其他

多项研究表明[15,19]，视网膜内或视网膜下出血可导致眼底血管造影术(fundus fluorescein angiography, FFA)荧光遮蔽，与纤维血管瘢痕形成的风险增加有关。这是由于出血会促进纤维蛋白网的收缩和纤维化的形成，且血液中的含铁血黄素的沉积会对光感受器产生铁毒性，从而引起中心视力的下降。Roberts等[8]使用PS-OCT发现，与没有纤维化的眼睛相比，有纤维化的眼睛在基线时存在更大的CNV最大线性直径(greatest linear diameter,GLD)和更大的CNV病变面积。此外，多项研究表明，较厚的视网膜与纤维化瘢痕形成相关。
总而言之，视网膜下纤维化的形成与患者的临床基线特征密切相关，因此，探寻影响wAMD患者视网膜下纤维化的基线特征，可以帮助预测患者的最终视力预后，制定更有个性化的治疗方案。

3 发病机制

视网膜下纤维化的形成机制目前尚不完全清楚，wAMD中的视网膜下纤维化是组织慢性损伤修复的结果，包含了三个阶段，即炎症反应、细胞增殖、ECM沉积和组织重塑。在组织损伤后不久，上皮细胞释放介质招募和激活炎症细胞、内皮细胞和成纤维细胞。此外，细胞经历上皮-间质转化，从而实现转分化，导致上皮细胞转化为肌成纤维细胞[26]。在wAMD中，新生血管易渗漏，会导致周围组织的慢性损伤，并形成含有大量炎症介质的环境。炎性细胞和肌成纤维细胞的招募、激活和增殖导致ECM的过度沉积和重塑,并在基底层增殖和迁移，覆盖和再生受损组织；最终，新生血管病变可能发展为纤维血管复合体，并形成黄斑纤维化，这一过程被称为血管纤维化转换[8]。

3.1 wAMD新生血管纤维化的细胞来源

肌成纤维细胞是纤维化发展的关键细胞，通过产生过量的ECM蛋白来促进纤维化的形成。由于黄斑中没有肌成纤维细胞，因此可以假设wAMD中的肌成纤维细胞是由肌成纤维细胞前体细胞发育而来的，如神经胶质细胞、RPE细胞、内皮细胞、巨噬细胞、脉络膜基质细胞等[27-28]，多种细胞可通过激活或转分化为肌成纤维细胞而导致wAMD中的黄斑纤维化。其中，经历EMT的RPE细胞被认为是肌成纤维细胞的主要来源，而破坏RPE的细胞-细胞接触是启动RPE发生EMT的关键步骤[29]。正常情况下，RPE保持成熟的上皮表型，有丝分裂静止，通过钙黏蛋白在相邻细胞上的同型黏附介导细胞间接触抑制。一旦这些接触被破坏，RPE细胞就会失去上皮表型，上皮标志物表达减少，而间质标志物的表达增加，从而获得间质特性[30]。在wAMD中，RPE的脱离和分离导致RPE细胞间接触的丧失，从而诱导EMT。此外，Müller细胞属于视网膜的胶质细胞，也可以分化为肌成纤维细胞[27,31]。

3.2 炎症反应

炎症反应，尤其是固有免疫系统细胞的浸润和激活，与wAMD视网膜下纤维化的发展密切相关[32]。尤其是髓样细胞，如血源性巨噬细胞和视网膜小胶质细胞，通过刺激与炎症反应有关的生长因子和细胞因子，参与了纤维化的形成[33]。巨噬细胞根据极化的功能亚型，可分为抗血管生成的经典激活型(M1)以及促血管生成的替代激活型(M2)[34]。M2巨噬细胞作为促纤维化效应因子，释放作用于成纤维细胞并增强ECM重塑的细胞因子；M1巨噬细胞通过释放促进ECM降解的基质金属蛋白酶(matrix metalloproteinase,MMP)来缓解和逆转纤维[35]。M1/M2巨噬细胞的比例可以调节MNV的发展。近年的研究表明[36]，活化的小胶质细胞表达的白细胞介素6(interleukin 6,IL-6)是促进视网膜下纤维化的关键介质，靶向IL-6和相应的信号通路在治疗MNV及视网膜下纤维化中都不失为一种有效的方法。

3.3 生长因子

前述研究提及，多种细胞通过分泌控制wAMD中细胞招募、增殖和死亡的生长因子从而促进纤维化的发展。
转化生长因子-β(transforming growth factor-β, TGF-β)在多种组织纤维化的过程中起着重要作用，其也可以通过诱导结缔组织生长因子(connective tissue growth factor,CTGF)等方式促进wAMD 纤维化[37]。CTGF可参与控制细胞增殖、分化、黏附和血管生成等过程以及肿瘤发展和组织纤维化等多种病理过程，在从伤口愈合到组织纤维化的过程中发挥着重要的作用。Daftarian等[38]在激光诱导的CNV模型中发现，抑制CTGF可显著减少视网膜下纤维化，表明了CTGF在wAMD和纤维化中的重要作用。
成纤维细胞生长因子(fibroblast growth factor,FGF)是一大类分泌分子，FGF家族由23个成员组成，其中22个在人类中发现[39]。FGF2在人类脉络膜新生血管膜中被发现可通过刺激TGFβ诱导RPE细胞的EMT。Matsuda等[40]在激光诱导的小鼠CNV模型中发现，FGF2的抑制与CNV的减少和视网膜下纤维化有关。
血小板衍生生长因子( platelet-der ived grow th factor,PDGF)是血管内稳态和周细胞分化的公认中枢介质，在调节人体的纤维化过程中起着关键作用。研究表明，在实验性CNV形成的早期阶段，周细胞和PDGF在内皮细胞支架形成中起着关键作用[41]，PDGF是对免疫细胞、RPE细胞和胶质细胞的有效化学诱导剂，在激光诱导的CNV小鼠模型中，通过阻断血小板衍生生长因子受体β(platelet-derived growth factor receptor β,PDGFRβ)来抑制PDGF信号，导致CNV形成和视网膜下纤维化的减少[42]。
除了上述被研究较多的生长因子外，IL-1β、IL-6和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)等炎症细胞因子也通过诱导内皮-间充质转化(endothelial-mesenchymal transition ,EndMT)参与了纤维化的过程[43]。

4 抗纤维化治疗

Anti-VEGF药物是治疗wAMD的一线药物，它显著降低了wAMD患者诊断后2年内的致盲率[44]，使大部分患者视力获益，但纤维化瘢痕和黄斑萎缩是仍是晚期wAMD患者视力无法提升甚至下降的重要原因。迄今为止，尚无明确的有效的抗纤维化治疗方法。临床试验表明，抗VEGF 单一疗法虽不能改善黄斑纤维化，但及时启动治疗可能有助于预防或延缓纤维化的进展[34]。Bloch等[45]发现，在患者确诊wAMD与第一次anti-VEGF治疗间隔<14 d时，相比间隔≥14 d的患者，形成视网膜下纤维化的风险更低。这主要可以解释为anti-VEGF治疗抑制血管生成和新生血管渗漏，从而减少免疫细胞的浸润，减轻炎症反应的程度。
由于纤维化的发生是最终视力预测的最重要因素，最近，已有许多研究通过抑制wAMD中的成纤维细胞增殖来限制视网膜下纤维化的形成。越来越多的分子介质可用于开发新型抗纤维化药物，如血小板内皮生长因子，炎症因子，转录因子抑制剂、免疫细胞调节剂等。其中被研究较多的分子介质，包括肾上腺髓质素(adrenomedullin,AM)(一种血管活性肽)及其受体活性修饰蛋白 2(receptor activity-modifying protein 2,RAMP2)、活化的巨噬细胞表达的 IL-6 、PDGF受体拮抗剂等被多次证实都是有效的潜在治疗靶点[46-48]。虽然靶向抑制PDGF等单一因子首次显示出有希望的临床结果，但瘢痕形成中多个信号通路的病理生理学过于复杂，似乎无法通过单独抑制单个因子取得相关的临床成功。未来可能需要利用作用于不同靶点的药物，将其联合治疗视网膜下纤维化。
而且，上述分子介质仅在实验模型中被证实可抑制视网膜下纤维化，这些药物的临床安全性及有效性还有待进一步研究。

5 总结

视网膜下纤维化是wAMD的晚期病理过程，一旦发生纤维化，视力将出现不可逆的丧失。识别与发生视网膜下纤维化相关的基线特征对于早期预测纤维化、制定针对患者视网膜下纤维化的个性化治疗方案至关重要。迄今为止，尚无有效的抗纤维化治疗方法。单纯anti-VEGF 治疗不能防止视网膜下纤维化的发展。越来越多研究正在尝试通过靶向wAMD 中的成纤维细胞增殖来限制瘢痕的形成，多种分子介质可用于开发抗纤维化药物，由于多种介质共同参与视网膜下纤维化的发病机制，多靶点联合治疗或比单一疗法更加有效。AMD的发病率不断升高，视网膜下纤维化的患者数量不断增加，未来对安全有效的抗纤维化药物的需求将越来越大。

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