Ultrastructural Changes Associated With Dexamethasone-Induced Ocular Hypertension in Mice
Ultrastructural Changes Associated With Dexamethasone-Induced Ocular Hypertension in Mice
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DOI：
10.1167/iovs.14-14429
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发表时间：
2014-08-01
影响因子：
4.4
通讯作者：
Luetjen-Drecoll, Elke
中科院分区：
文献类型：
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作者：
Overby, Darryl R.;Bertrand, Jacques;Luetjen-Drecoll, Elke
目的.确定地塞米松（DEX）诱导的小鼠高眼压（OHT）是否模仿人类类固醇诱导的青光眼（SIG）的特征，包括常规流出道功能（C）降低、细胞外基质（ECM）增加和流出道内的肌成纤维细胞。将渗透微型泵皮下植入C57 BL/6 J小鼠中，用于全身递送DEX（3-4 mg/kg/d，n = 31只小鼠）或媒介物（n = 28）。每周通过反跳眼压计测量IOP。3 - 4周后，对小鼠实施安乐死并摘除眼睛，用于离体灌注以测量C，用于电子显微镜检查小梁网（TM）和施累姆氏管（SC），或用于免疫组织化学检查IV型胶原和α-平滑肌肌动蛋白。电镜下沿SC前后方向沿着测量基底膜物质（BMM）的长度。将DEX处理的小鼠的BMM中的超微结构变化与存档的人SIG受体进行比较。与对照组相比，地塞米松在3 - 4周内使IOP增加2.6 ± 1.6 mm Hg（平均值± SD），并使C降低52% ± 17%。眼压升高与C.地塞米松治疗导致TM中的纤维状材料、弹性纤维周围的斑块样鞘材料和沿着SC外壁的肌成纤维细胞增加。DEX组小鼠和SIG组人类SC下的BMM长度显著增加，小鼠中C减少与BMM增加相关。地塞米松诱导的小鼠OHT在DEX治疗的4周内模拟人SIG的标志。减少的C和新形成的ECM之间的相关性激发了使用DEX处理的小鼠来研究青光眼中常规流出道阻塞的发病机制的进一步研究。
PURPOSE. To determine whether dexamethasone (DEX)-induced ocular hypertension (OHT) in mice mimics the hallmarks of steroid-induced glaucoma (SIG) in humans, including reduced conventional outflow facility (C), increased extracellular matrix (ECM), and myofibroblasts within the outflow pathway.METHODS. Osmotic mini-pumps were implanted subcutaneously into C57BL/6J mice for systemic delivery of DEX (3-4 mg/kg/d, n = 31 mice) or vehicle (n = 28). IOP was measured weekly by rebound tonometry. After 3 to 4 weeks, mice were euthanized and eyes enucleated for ex vivo perfusion to measure C, for electron microscopy to examine the trabecular meshwork (TM) and Schlemm's canal (SC), or for immunohistochemistry to examine type IV collagen and a-smooth muscle actin. The length of basement membrane material (BMM) was measured along the anterior-posterior extent of SC by electron microscopy. Ultrastructural changes in BMM of DEX-treated mice were compared against archived human SIG specimens.RESULTS. Dexamethasone increased IOP by 2.6 +/- 1.6 mm Hg (mean +/- SD) over 3 to 4 weeks and decreased C by 52% +/- 17% versus controls. Intraocular pressure elevation correlated with decreased C. Dexamethasone treatment led to increased fibrillar material in the TM, plaque-like sheath material surrounding elastic fibers, and myofibroblasts along SC outer wall. The length of BMM underlying SC was significantly increased in mice with DEX and in humans with SIG, and in mice decreased C correlated with increased BMM.CONCLUSIONS. Dexamethasone-induced OHT in mice mimics hallmarks of human SIG within 4 weeks of DEX treatment. The correlation between reduced C and newly formed ECM motivates further study using DEX-treated mice to investigate the pathogenesis of conventional outflow obstruction in glaucoma.