Protective effects of dexamethasone on hypoxia-induced retinal edema in a mouse model
Protective effects of dexamethasone on hypoxia-induced retinal edema in a mouse model
复制标题
DOI：
10.1016/j.exer.2018.09.014
复制
发表时间：
2019-01-01
影响因子：
3.4
通讯作者：
Ito, Masataka
中科院分区：
文献类型：
--
作者：
Inada, Makoto;Taguchi, Manzo;Ito, Masataka
缺氧诱导的视网膜水肿主要由血管病变引起，见于各种疾病，如糖尿病视网膜病变（DR）和视网膜静脉阻塞（RVO）。这些病症中的水肿性变化主要发生在视网膜的中间层和深层中，这是由于内部血视网膜屏障（iBRB）的破坏。然而，直接和急性缺氧对iBRB的影响仍有待阐明。为了研究直接和急性缺氧诱导的视网膜变化，特别是参与维持视网膜结构和功能的星形胶质细胞/Muller细胞，我们开发了一种在6%氧环境中暴露24小时的缺氧诱导视网膜水肿的成年小鼠模型。胶质细胞酸性蛋白（GFAP）的免疫组化染色主要在缺氧视网膜的浅层增强，与水肿改变相对应。电镜下可见视网膜浅层毛细血管周围星形胶质细胞/Muller细胞足突内空泡形成，中层和深层血管周围未见异常改变。缺氧组血管渗漏增加（伊文思蓝染色）和紧密连接破坏（电子致密示踪剂）。在缺氧视网膜中，小胶质细胞被激活，促炎细胞因子的相关基因表达显著上调。地塞米松抑制这些缺氧引起的病理反应。因此，与诱导视网膜深层iBRB破坏的DR和RVO不同，大气缺氧诱导iBRB破坏，随后主要在视网膜浅层发生水肿变化，地塞米松可预防这些病理变化。在该小鼠模型中，直接和急性缺氧诱导视网膜浅层中的视网膜水肿，伴有星形胶质细胞/Muller细胞的形态学变化，并且在与视网膜缺氧及其治疗相关的领域中的眼科研究中具有潜在的用途。
Hypoxia-induced retinal edema primarily induced by vascular lesion is seen in various conditions such as diabetic retinopathy (DR) and retinal vein occlusion (RVO). The edematous changes in these conditions occur mainly in intermediate and deep layers of retina as a result of disruption of the inner blood-retinal barrier (iBRB). However, the effect of direct and acute hypoxia on iBRB remains to be elucidated. To investigate direct and acute hypoxia-induced changes in retina, especially in astrocytes/Muller cells that are involved in the maintenance of retinal structure and function, we developed an adult mouse model of hypoxia-induced retinal edema by 24-h exposure in a 6% oxygen environment. Immunohistochemical staining of glial fibrillary acidic protein (GFAP) was enhanced mainly in the superficial layer of the hypoxic retina, corresponding to edematous change. Electron microscopic observation of the hypoxic retina showed vacuole formation in astrocyte/Muller cell foot processes around capillaries in the superficial layer, while no abnormal findings in the perivascular areas were found in intermediate and deep layers. Increase in vascular leakage quantified by Evans blue dye and tight junction breakdown detected by electron-dense tracer were observed in the hypoxia group. In the hypoxic retina, microglia was activated and relative gene expressions of pro-inflammatory cytokines were significantly upregulated. Dexamethasone suppressed these hypoxia-induced pathological reactions. Thus, unlike DR and RVO that induce iBRB breakdown in deeper retinal layers, atmospheric hypoxia induced iBRB disruption with subsequent edematous change mainly in the superficial layer of the retina, and that dexamethasone prevented these pathological changes. In this mouse model, direct and acute hypoxia induces retinal edema in the superficial layer of the retina with morphological changes of astrocytes/Muller cells, and is potentially useful for ophthalmic research in the field related to retinal hypoxia and its treatment.