Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China; National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Exp Eye Res. 2021 Feb;203:108417. doi: 10.1016/j.exer.2020.108417. Epub 2020 Dec 29.
Age-related macular degeneration (AMD) is a leading cause of blindness. Laser-induced nonhuman primate choroidal neovascularization (CNV) is a widely used animal model of neovascular AMD. Subretinal fibrosis (SFb) is the major limiting factor of effective anti-VEGF therapy for neovascular AMD, yet SFb has never been systematically analyzed in the primate CNV model and if VEGF directly affect SFb is unknown. We recruited a large cohort of rhesus macaques to study the occurrence, multimodal imaging and electroretinography (ERG) features, and related cytokines of SFb. Here we show that among 33 rhesus macaques, 88% CNV eyes developed SFb. Spectral domain optical coherence tomography (SD-OCT) identified four types of subretinal hyper-reflective material (SHRM) of SFb in primate. Multimodal imaging is reliable for monitoring SFb and matches the histological results well. Reduced amplitude of oscillatory potentials correlates with the thinning of inner retina layers and is a possible SFb indicator. Iba1 microglia/macrophage cells infiltrated in the fibrotic lesions, and aqueous cytokine analysis identified four fibrosis-related factors (GM-CSF, IL-10, TGFβ2 and VEGF). Unexpectedly, we found sustained expression of VEGF may be an important inducer of SFb, and anti-VEGF therapy actually partially suppresses SFb. Taken together, our data suggest the laser-induced primate SFb model, coupled with multimodal imaging and ERG recording, is a useful system to dissect the pathogenesis and explore the rationale of treatment for SFb; and combined therapy with anti-VEGF and anti-fibrosis agents is necessary for AMD treatment.
年龄相关性黄斑变性（AMD）是导致失明的主要原因。激光诱导的非人灵长类脉络膜新生血管（CNV）是一种广泛应用于新生血管性 AMD 的动物模型。脉络膜新生血管性 AMD 有效的抗血管内皮生长因子（VEGF）治疗的主要限制因素是视网膜下纤维化（SFb），但在灵长类动物 CNV 模型中从未对 SFb 进行过系统分析，也不知道 VEGF 是否直接影响 SFb。我们招募了大量的恒河猴来研究 SFb 的发生、多模态成像和视网膜电图（ERG）特征以及相关细胞因子。结果显示，在 33 只恒河猴中，88%的 CNV 眼发生了 SFb。光谱域光学相干断层扫描（SD-OCT）在灵长类动物中识别出了 SFb 的四种类型的视网膜下高反射物质（SHRM）。多模态成像可用于监测 SFb，与组织学结果吻合良好。振荡电位幅度的降低与内层视网膜变薄相关，是 SFb 的一个可能的指标。Iba1 小胶质细胞/巨噬细胞浸润在纤维化病变中，房水细胞因子分析鉴定出四个与纤维化相关的因子（GM-CSF、IL-10、TGFβ2 和 VEGF）。出乎意料的是，我们发现 VEGF 的持续表达可能是 SFb 的一个重要诱导因素，而抗 VEGF 治疗实际上部分抑制了 SFb。综上所述，我们的数据表明，激光诱导的灵长类 SFb 模型结合多模态成像和 ERG 记录，是一种用于剖析 SFb 发病机制和探索治疗方案合理性的有用系统；AMD 治疗需要联合使用抗 VEGF 和抗纤维化药物。
