Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI.
Mol Vis. 2020 Apr 1;26:257-276. eCollection 2020.
Retinopathy of prematurity (ROP) is a condition of aberrant retinal vascularization in premature infants in response to high levels of oxygen used for critical care that can potentially cause blindness. Although therapies to mitigate vascular abnormalities are being evaluated, functional deficits often remain in patients with treated or regressed ROP. This study investigated long-term outcomes of hyperoxia on retinal morphology and function using a mouse model of oxygen-induced ischemic retinopathy (OIR).
Twenty-two mice were exposed to 77% oxygen to induce OIR, while 23 age-matched control mice were raised in room air (RA). In vivo fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), and focal electroretinography (fERG) were performed at P19, P24, P32, and P47, followed by histological assessments of retinal morphology, gliosis, microglia activation, and apoptosis.
FA in OIR mice showed capillary attrition despite peripheral revascularization. Inner retina thinning was detected with SD-OCT; outer and inner retinal dysfunction were demonstrated with fERG. Histology of the OIR mice exhibited a thin, disorganized structure. Immunohistochemistry showed increased gliosis, microglial activation, and apoptosis with increasing age from P19 to P47. The synapses between rod photoreceptor cells and rod bipolar cells were ectopically localized in the OIR mice.
We demonstrated histological evidence of persistent ectopic synapses, prolonged cellular apoptosis, and gliosis in the OIR retina that corresponded with long-term in vivo evidence of capillary attrition, inner retinal thinning, and dysfunction despite full peripheral revascularization. Further studies on the mechanisms underlying these persistent phenotypes could enhance our understanding of ROP pathogenesis and lead to new therapeutic targets to preserve visual function in premature infants.
早产儿视网膜病变（ROP）是一种早产儿视网膜血管异常增生的疾病，是对接受重症监护的早产儿使用高浓度氧气治疗的结果，这种疾病可能导致失明。虽然有多种治疗方法可以减轻血管异常，但接受治疗或病变消退的 ROP 患者通常仍存在功能缺陷。本研究使用氧诱导缺血性视网膜病变（OIR）的小鼠模型，研究了高氧对视网膜形态和功能的长期影响。
将 22 只小鼠暴露于 77%的氧气中以诱导 OIR，同时将 23 只年龄匹配的对照小鼠置于室内空气中（RA）。在 P19、P24、P32 和 P47 时进行活体荧光素血管造影（FA）、谱域光学相干断层扫描（SD-OCT）和焦点视网膜电图（fERG）检查，然后进行视网膜形态、神经胶质增生、小胶质细胞激活和细胞凋亡的组织学评估。
OIR 小鼠的 FA 显示尽管有周边血管再生，但毛细血管萎缩。SD-OCT 检测到内视网膜变薄；fERG 显示外和内视网膜功能障碍。OIR 小鼠的组织学检查显示出薄而紊乱的结构。免疫组织化学显示，从 P19 到 P47，随着年龄的增长，神经胶质增生、小胶质细胞激活和细胞凋亡增加。杆状光感受器细胞和杆状双极细胞之间的突触在 OIR 小鼠中异位定位。
我们证明了在 OIR 视网膜中存在持续的异位突触、延长的细胞凋亡和神经胶质增生的组织学证据，这与毛细血管萎缩、内视网膜变薄和功能障碍的长期活体证据一致，尽管有完全的周边血管再生。对这些持续表型背后的机制进行进一步研究，可能会增强我们对 ROP 发病机制的理解，并为保护早产儿的视觉功能提供新的治疗靶点。
