Department of Ophthalmic Research, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States.
Eversight, Cleveland, Ohio, United States.
Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):36. doi: 10.1167/iovs.61.13.36.
Retinopathy of prematurity (ROP) is a severe complication of premature infants, leading to vision loss when untreated. Presently, the molecular mechanisms underlying ROP are still far from being clearly understood. This study sought to investigate whether thyroid hormone (TH) signaling contributes to the neuropathology of ROP using the mouse model of ROP to evaluate longitudinal photoreceptor function.
Animals were exposed to hyperoxia from P7 to P12 to induce retinopathy, thereafter the animals were returned to room air (normoxia). The thyroid-activating enzyme type 2 deiodinases (Dio2) knockout (KO) mice and the littermate controls that were exposed to hyperoxia or maintained in room air and were then analyzed. The retinal function was evaluated using electroretinograms (ERGs) at three and seven weeks followed by histologic assessments with neuronal markers to detect cellular changes in the retina. Rhodopsin protein levels were measured to validate the results obtained from the immunofluorescence analyses.
In the ROP group, the photoreceptor ERG responses are considerably lower both in the control and the Dio2 KO animals at P23 compared to the non-ROP group. In agreement with the ERG responses, loss of Dio2 results in mislocalized cone nuclei, and abnormal rod bipolar cell dendrites extending into the outer nuclear layer. The retinal function is compromised in the adult Dio2 KO animals, although the cellular changes are less severe. Despite the reduction in scotopic a-wave amplitudes, rhodopsin levels are similar in the adult mice, across all genotypes irrespective of exposure to hyperoxia.
Using the mouse model of ROP, we show that loss of Dio2 exacerbates the effects of hyperoxia-induced retinal deficits that persist in the adults. Our data suggest that aberrant Dio2/TH signaling is an important factor in the pathophysiology of the visual dysfunction observed in the oxygen-induced retinopathy model of ROP.
早产儿视网膜病变（ROP）是早产儿的一种严重并发症，未经治疗会导致视力丧失。目前，ROP 的分子机制仍远未被清楚地理解。本研究旨在使用 ROP 小鼠模型来评估长时程光感受器功能，以研究甲状腺激素（TH）信号是否有助于 ROP 的神经病理学。
动物从 P7 至 P12 暴露于高氧环境中以诱导视网膜病变，然后将动物返回室内空气（常氧）环境。对暴露于高氧或维持在室内空气环境中的甲状腺激活酶 2 型脱碘酶（Dio2）敲除（KO）小鼠及其同窝对照小鼠进行分析。使用视网膜电图（ERG）在 3 周和 7 周时评估视网膜功能，然后用神经元标志物进行组织学评估，以检测视网膜中的细胞变化。测量视紫红质蛋白水平以验证免疫荧光分析的结果。
在 ROP 组中，与非 ROP 组相比，在 P23 时，对照组和 Dio2 KO 动物的光感受器 ERG 反应均明显降低。与 ERG 反应一致，Dio2 的缺失导致锥体核的异位定位，以及异常的杆状双极细胞树突延伸到外核层。尽管在成年 Dio2 KO 动物中视网膜功能受损，但细胞变化较轻。尽管暗视 a 波幅度降低，但在所有基因型的成年小鼠中，视紫红质水平相似，无论是否暴露于高氧环境。
使用 ROP 小鼠模型，我们表明 Dio2 的缺失加剧了高氧诱导的视网膜缺陷的影响，这些影响在成年期仍然存在。我们的数据表明，异常的 Dio2/TH 信号是氧诱导的 ROP 视网膜病变模型中观察到的视觉功能障碍的病理生理学的重要因素。
