Department of Ophthalmology, Stanford University, School of Medicine, Stanford, CA, USA.
Department of Pulmonary Medicine, Stanford University, School of Medicine, Stanford, CA, USA.
Exp Eye Res. 2020 Apr;193:107957. doi: 10.1016/j.exer.2020.107957. Epub 2020 Feb 4.
Vision loss is a devastating consequence of systemic hypoxia, but the cellular mechanisms are unclear. We investigated the impact of acute hypoxia in the retina and optic nerve. We induced systemic hypoxia (10% O) in 6-8w mice for 48 h and performed in vivo imaging using optical coherence tomography (OCT) at baseline and after 48 h to analyze structural changes in the retina and optic nerve. We analyzed glial cellular and molecular changes by histology and immunofluorescence and the impact of pretreatment with 4-phenylbutyric acid (4-PBA) in oligodendroglia survival. After 48 h hypoxia, we found no change in ganglion cell complex thickness and no loss of retinal ganglion cells. Despite this, there was significantly increased expression of CCAAT-enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum stress, in the retina and optic nerve. In addition, hypoxia induced obvious increase of GFAP expression in the anterior optic nerve, where it co-localized with CHOP, and significant loss of Olig2 oligodendrocytes. Pretreatment with 4-PBA, which has been shown to reduce endoplasmic reticulum stress, rescued total Olig2 oligodendrocytes and increased the pool of mature (CC-1) but not of immature (PDGFRa+) oligodendrocytes. Consistent with a selective vulnerability of the retina and optic nerve in hypoxia, the most striking changes in the 48 h murine model of hypoxia were in glial cells in the optic nerve, including increased CHOP expression in the astrocytes and loss of oligodendrocytes. Our data support a model where glial dysfunction is among the earliest events in systemic hypoxia - suggesting that glia may be a novel target in treatment of hypoxia.
视力丧失是全身缺氧的严重后果，但细胞机制尚不清楚。我们研究了视网膜和视神经急性缺氧的影响。我们在 6-8 周龄的小鼠中诱导全身缺氧（10% O）48 小时，并在基线和 48 小时后使用光学相干断层扫描（OCT）进行体内成像，以分析视网膜和视神经的结构变化。我们通过组织学和免疫荧光分析了神经胶质细胞的形态和分子变化，并研究了 4-苯丁酸（4-PBA）预处理对少突胶质细胞存活的影响。缺氧 48 小时后，我们发现神经节细胞复合体厚度没有变化，也没有视网膜神经节细胞丢失。尽管如此，视网膜和视神经中 CCAAT 增强子结合蛋白同源蛋白（CHOP）的表达显著增加，CHOP 是内质网应激的标志物。此外，缺氧诱导了前视神经中 GFAP 表达的明显增加，GFAP 与 CHOP 共定位，并导致明显的少突胶质细胞 Olig2 丢失。已经表明，4-PBA 预处理可减少内质网应激，挽救总 Olig2 少突胶质细胞，并增加成熟（CC-1）但不增加未成熟（PDGFRa+）少突胶质细胞的池。与缺氧时视网膜和视神经的选择性易损性一致，缺氧 48 小时小鼠模型中最显著的变化是视神经中的神经胶质细胞，包括星形胶质细胞中 CHOP 表达增加和少突胶质细胞丢失。我们的数据支持这样一种模型，即神经胶质功能障碍是全身缺氧最早发生的事件之一 - 这表明神经胶质细胞可能是治疗缺氧的新靶点。
