Kenneth C. Swan Ocular Neurobiology Laboratory, Casey Eye Institute, Oregon Health and Science University, Portland, Oregon 97201, USA.
Invest Ophthalmol Vis Sci. 2011 Jan 25;52(1):504-18. doi: 10.1167/iovs.10-5317. Print 2011 Jan.
In glaucoma, the optic nerve head (ONH) is the principal site of initial axonal injury, and elevated intraocular pressure (IOP) is the predominant risk factor. However, the initial responses of the ONH to elevated IOP are unknown. Here the authors use a rat glaucoma model to characterize ONH gene expression changes associated with early optic nerve injury.
Unilateral IOP elevation was produced in rats by episcleral vein injection of hypertonic saline. ONH mRNA was extracted, and retrobulbar optic nerve cross-sections were graded for axonal degeneration. Gene expression was determined by microarray and quantitative PCR (QPCR) analysis. Significantly altered gene expression was determined by multiclass analysis and ANOVA. DAVID gene ontology determined the functional categories of significantly affected genes.
The Early Injury group consisted of ONH from eyes with <15% axon degeneration. By array analysis, 877 genes were significantly regulated in this group. The most significant upregulated gene categories were cell cycle, cytoskeleton, and immune system process, whereas the downregulated categories included glucose and lipid metabolism. QPCR confirmed the upregulation of cell cycle-associated genes and leukemia inhibitory factor (Lif) and revealed alterations in expression of other IL-6-type cytokines and Jak-Stat signaling pathway components, including increased expression of IL-6 (1553%). In contrast, astrocytic glial fibrillary acidic protein (Gfap) message levels were unaltered, and other astrocytic markers were significantly downregulated. Microglial activation and vascular-associated gene responses were identified.
Cell proliferation and IL-6-type cytokine gene expression, rather than astrocyte hypertrophy, characterize early pressure-induced ONH injury.
在青光眼患者中，视神经头部（ONH）是最初轴突损伤的主要部位，眼内压升高（IOP）是主要的危险因素。然而，ONH 对IOP 升高的最初反应尚不清楚。作者在这里使用大鼠青光眼模型来描述与早期视神经损伤相关的 ONH 基因表达变化。
通过巩膜静脉注射高渗盐水在大鼠中产生单侧 IOP 升高。提取 ONH mRNA，并对眶后视神经横切片进行轴突变性分级。通过微阵列和定量 PCR（QPCR）分析确定基因表达。通过多类分析和 ANOVA 确定显著改变的基因表达。DAVID 基因本体论确定了受显著影响基因的功能类别。
早期损伤组由视神经头部组成，其轴突退变<15%。通过阵列分析，该组有 877 个基因显著调节。上调最显著的基因类别是细胞周期、细胞骨架和免疫系统过程，而下调的类别包括葡萄糖和脂质代谢。QPCR 证实了细胞周期相关基因和白血病抑制因子（Lif）的上调，并揭示了其他 IL-6 型细胞因子和 Jak-Stat 信号通路成分表达的改变，包括 IL-6（1553%）的表达增加。相比之下，星形胶质细胞胶质纤维酸性蛋白（Gfap）的 mRNA 水平没有改变，其他星形胶质细胞标志物显著下调。识别到小胶质细胞激活和血管相关基因的反应。
细胞增殖和 IL-6 型细胞因子基因表达，而不是星形胶质细胞肥大，是特征性的早期压力诱导的 ONH 损伤。
