Proinflammatory Cytokines Are Involved in the Initiation of the Abnormal Matrix Process in Pseudoexfoliation Syndrome/Glaucoma
Proinflammatory Cytokines Are Involved in the Initiation of the Abnormal Matrix Process in Pseudoexfoliation Syndrome/Glaucoma
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DOI：
10.2353/ajpath.2010.090914
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发表时间：
2010-06-01
影响因子：
6
通讯作者：
Schloetzer-Schrehardt, Ursula
中科院分区：
文献类型：
--
作者：
Zenkel, Matthias;Lewczuk, Piotr;Schloetzer-Schrehardt, Ursula
假性剥脱（PEX）综合征是一种与年龄相关的全身性弹性基质过程，目前是开角型青光眼最常见的可识别危险因素。促炎细胞因子的表达失调与各种纤维化疾病的发生和青光眼的病理生理学有关。在这里，我们使用多重微珠分析、免疫测定、实时 PCR、蛋白质印迹、免疫组织化学和细胞培养模型，与正常和青光眼对照眼睛相比，研究了早期和晚期 PEX 综合征/青光眼眼睛中促炎细胞因子的存在、表达、调节和功能意义。与对照组相比，PEX 综合征早期阶段的特点是房水中白细胞介素 (IL)-6 和 IL-8 水平升高约三倍 (P < 0.005)，并且眼前节组织中 mRNA 表达水平随之升高约两倍 (P < 0.001)。相比之下，PEX 综合征/青光眼的晚期阶段与对照组没有显着差异。 IL-6、IL-6 受体以及磷酸信号转导器和转录激活剂 3 可能主要定位于虹膜血管壁和睫状突的非色素上皮。体外缺氧或氧化应激时，睫状上皮细胞显着上调 IL-6 和 IL-8，而 IL-6（而非 IL-8）诱导转化生长因子-β 1 和弹性纤维蛋白的表达。这些发现支持压力诱导的、空间和时间限制的亚临床炎症在 PEX 综合征/青光眼的纤维化基质过程特征的发生中的作用。 （Am J Pathol 2010，176：2868-2879；DOI：10.2353/typath.2010.090914）
Pseudoexfoliation (PEX) syndrome, which is an age-related, generalized elastotic matrix process, currently represents the most common identifiable risk factor for open-angle glaucoma. Dysregulated expression of proinflammatory cytokines has been implicated in the initiation of various fibrotic disorders and in the pathophysiology of glaucoma. Here we investigated the presence, expression, regulation, and functional significance of proinflammatory cytokines in eyes with early and late stages of PEX syndrome/glaucoma in comparison with normal and glaucomatous control eyes using multiplex bead analysis, immunoassays, real-time PCR, Western blotting, immunohistochemistry, and cell culture models. Early stages of PEX syndrome were characterized by approximately threefold (P < 0.005) elevated interleukin (IL)-6 and IL-8 levels in the aqueous humor and a concomitant approximately twofold (P < 0.001) increase in mRNA expression levels in anterior segment tissues as compared with controls. In contrast, late stages of PEX syndrome/glaucoma did not differ significantly from controls. IL-6, IL-6 receptor, and phospho-signal transducer and activator of transcription 3 could be mainly localized to walls of iris vessels and to the nonpigmented epithelium of ciliary processes. IL-6 and IL-8 were significantly up-regulated by ciliary epithelial cells in response to hypoxia or oxidative stress in vitro, whereas IL-6, but not IL-8, induced the expression of transforming growth factor-beta 1 and elastic fiber proteins. These findings support a role for a stress-induced, spatially, and temporally restricted subclinical inflammation in the onset of the fibrotic matrix process characteristic of PEX syndrome/glaucoma. (Am J Pathol 2010, 176:2868-2879; DOI: 10.2353/typath.2010.090914)