Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix
Dexamethasone Stiffens Trabecular Meshwork, Trabecular Meshwork Cells, and Matrix
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DOI：
10.1167/iovs.15-16739
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发表时间：
2015-07-01
影响因子：
4.4
通讯作者：
Russell, Paul
中科院分区：
文献类型：
--
作者：
Raghunathan, Vijay Krishna;Morgan, Joshua T.;Russell, Paul
目的。皮质类固醇治疗可导致高眼压，并可能导致类固醇性青光眼的发展。小梁网（TM）细胞和细胞外基质（ECM）的生物力学变化对这种功能障碍的影响程度尚不清楚。将原代人TM （HTM）细胞在地塞米松（DEX）存在或不存在的情况下培养3天或4周，分别测定细胞力学、基质力学和蛋白质组学。用0.1% DEX或载药局部治疗成年家兔3周，观察TM的力学变化。DEX治疗3天导致HTM细胞硬度增加2倍，这与细胞外信号相关激酶1/2 （ERK1/2）的激活和a-平滑肌肌动蛋白（α SMA）的过度表达有关。此外，经DEX长期处理的HTM细胞沉积的基质硬度约为原来的4倍，更有组织，并且青光眼中常见的基质蛋白（decorin，心肌蛋白，纤维蛋白，分泌的卷曲相关蛋白[SFRP1]， matrix- glass）的表达升高。此外，DEX治疗导致兔颞叶僵硬度增加3.5倍。这种综合方法清楚地表明，DEX治疗增加了TM细胞的硬度，同时增加了aSMA的表达和丝裂原活化蛋白激酶（MAPK）途径的激活；在体外，随着Wnt拮抗剂和嵌入在更有组织的基质中的纤维化标志物的上调，ECM变硬；在体内，增加了TM组织的硬度。这些结果表明，糖皮质激素治疗可以引发与房水流出阻力增加相关的生物物理改变，从而导致IOP升高。
PURPOSE. Treatment with corticosteroids can result in ocular hypertension and may lead to the development of steroid-induced glaucoma. The extent to which biomechanical changes in trabecular meshwork (TM) cells and extracellular matrix (ECM) contribute toward this dysfunction is poorly understood.METHODS. Primary human TM (HTM) cells were cultured for either 3 days or 4 weeks in the presence or absence of dexamethasone (DEX), and cell mechanics, matrix mechanics and proteomics were determined, respectively. Adult rabbits were treated topically with either 0.1% DEX or vehicle over 3 weeks, and mechanics of the TM were determined.RESULTS. Treatment with DEX for 3 days resulted in a 2-fold increase in HTM cell stiffness, and this correlated with activation of extracellular signal-related kinase 1/2 (ERK1/2) and overexpression of a-smooth muscle actin (alpha SMA). Further, the matrix deposited by HTM cells chronically treated with DEX is approximately 4-fold stiffer, more organized, and has elevated expression of matrix proteins commonly implicated in glaucoma (decorin, myocilin, fibrillin, secreted frizzle-related protein [SFRP1], matrix-gla). Also, DEX treatment resulted in a 3.5-fold increase in stiffness of the rabbit TM.DISCUSSION. This integrated approach clearly demonstrates that DEX treatment increases TM cell stiffness concurrent with elevated aSMA expression and activation of the mitogen-activated protein kinase (MAPK) pathway, stiffens the ECM in vitro along with upregulation of Wnt antagonists and fibrotic markers embedded in a more organized matrix, and increases the stiffness of TM tissues in vivo. These results demonstrate glucocorticoid treatment can initiate the biophysical alteration associated with increased resistance to aqueous humor outflow and the resultant increase in IOP.