Unfolded Protein Response in Fuchs Endothelial Corneal Dystrophy: A Unifying Pathogenic Pathway?
Unfolded Protein Response in Fuchs Endothelial Corneal Dystrophy: A Unifying Pathogenic Pathway?
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DOI：
10.1016/j.ajo.2009.09.009
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发表时间：
2010-02-01
影响因子：
4.2
通讯作者：
Jun, Albert S.
中科院分区：
文献类型：
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作者：
Engler, Christoph;Kelliher, Clare;Jun, Albert S.
目的：探讨Fuchs内皮性角膜营养不良患者角膜内皮中未折叠蛋白反应的激活情况。设计：回顾性对比病例系列实验标本。方法：对Fuchs内皮性角膜营养不良患者和非Fuchs内皮性角膜营养不良患者的角膜标本进行透射电子显微镜观察，观察角膜内皮粗面内质网的结构变化。以粗面内质网的改变作为未折叠蛋白反应的标志，对电子显微镜图像进行评估。取正常尸检眼、Fuchs营养不良角膜和圆锥角膜进行免疫组织化学染色。对福尔马林固定、石蜡包埋的患者角膜切片进行免疫组织化学染色，检测3种未折叠的蛋白反应标志物(GRP78，真核细胞起始因子2的α亚单位，C/EBP同源蛋白)和2种细胞凋亡标志物(caspase3和9)。应用自动化软件对角膜内皮细胞进行免疫组织化学信号定量，以评估标志物的表达。结果：所有Fuchs营养不良患者的角膜内皮细胞均有粗面内质网增大。免疫组织化学定量显示Fuchs营养不良患者角膜内皮细胞标记GRP78、真核细胞起始因子2α亚单位、C/EBP同源蛋白和caspase9的平均信号显著高于非Fuchs营养不良角膜(P<；0.05)。结论：透射电子显微镜和免疫组织化学结果均显示Fuchs营养不良患者角膜内皮中未折叠蛋白反应被激活。未折叠蛋白反应激活导致Fuchs营养不良时内皮细胞的凋亡，可能在本病中起中心致病作用。《眼科杂志》2010；149：194-202。(C)2010年，爱思唯尔公司保留所有权利。)
PURPOSE: To assess for activation of the unfolded protein response in corneal endothelium of Fuchs endothelial corneal dystrophy patients.DESIGN: Retrospective, comparative case series of laboratory specimens.METHODS: Corneal specimens of patients with Fuchs dystrophy and controls with corneal pathologic features other than Fuchs dystrophy were evaluated by transmission electron microscopy (TEM) to evaluate for structural changes of the rough endoplasmic reticulum in corneal endothelium. TEM images were evaluated for alterations of rough endoplasmic reticulum as a sign of unfolded protein response. Normal autopsy eyes, Fuchs dystrophy corneas, and keratoconus corneas were used for immunohistochemistry. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections of patient corneas for 3 unfolded protein response markers (GRP78, the a subunit of eukaryotic initiation factor 2, C/EBP homologous protein) and 2 apoptosis markers (caspase 3 and 9). Immunohistochemistry signal quantitation of corneal endothelium for evaluation of marker expression was performed using automated software. Corneal sections were assessed quantitatively for levels of immunohistochemistry marker expression.RESULTS: TEM showed enlargement of rough endoplasmic reticulum in corneal endothelium of all Fuchs dystrophy specimens. Immunohistochemistry quantitation demonstrated a significant increase in mean signal in corneal endothelium from Fuchs dystrophy patients for markers GRP78, the a subunit of eukaryotic initiation factor 2, C/EBP homologous protein, and caspase 9 compared with non-Fuchs dystrophy corneas (P < .05).CONCLUSIONS: Results of both TEM and immunohistochemistry indicate activation of unfolded protein response in Fuchs dystrophy. Unfolded protein response activation leads to endothelial cell apoptosis in Fuchs dystrophy and may play a central pathogenic role in this disease. (Am J Ophthalmol 2010;149:194-202. (C) 2010 by Elsevier Inc. All rights reserved.)