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% O2) 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.

中文翻译：

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全身缺氧导致少量视网膜神经元损失和剧烈的视神经胶质反应。

视力丧失是全身缺氧的破坏性后果，但其细胞机制尚不清楚。我们研究了急性缺氧对视网膜和视神经的影响。我们在 6-8 周小鼠中诱导全身缺氧 (10% O2) 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和分子的变化，以及 4-苯基丁酸 (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，视网膜神经节细胞也没有损失。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) 的表达显着增加，CHOP 是内质网应激的标志物。此外，缺氧诱导前视神经中 GFAP 表达明显增加（与 CHOP 共定位），以及 Olig2+ 少突胶质细胞显着损失。4-PBA 预处理已被证明可以减少内质网应激，挽救 Olig2+ 少突胶质细胞总数，并增加成熟 (CC-1+) 的数量，但不增加未成熟 (PDGFRa+) 少突胶质细胞的数量。与缺氧时视网膜和视神经的选择性脆弱性一致，缺氧 48 小时小鼠模型中最显着的变化是视神经中的胶质细胞，包括星形胶质细胞中 CHOP 表达增加和少突胶质细胞损失。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的最早事件之一，这表明神经胶质细胞可能是治疗缺氧的新靶点。