McKee Clayton T, Wood Joshua A, Shah Nihar M, Fischer Marion E, Reilly Christopher M, Murphy Christopher J, Russell Paul
Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
Biomaterials. 2011 Mar;32(9):2417-23. doi: 10.1016/j.biomaterials.2010.11.071. Epub 2011 Jan 8.
Glaucoma is a devastating neurodegenerative disease, which can lead to vision loss and is associated with irreversible damage to retinal ganglion cells. Although the mechanism of disease onset remains unknown, we have recently demonstrated that the stiffness of the ocular trabecular meshwork (HTM) increases dramatically in human donor eyes with a history of glaucoma. Here we report that polyacrylamide hydrogels, which mimic the compliant conditions of normal and glaucomatous HTM, profoundly modulate cytoskeletal dynamics and the elastic modulus of the overlying HTM cells. Substratum compliance also modulates HTM cell response to Latrunculin-B, a cytoskeletal disrupting agent currently in human clinical trials for the treatment of glaucoma. Additionally, we observed a compliance-dependent rebound effect of Latrunculin-B with an unexpected increase in HTM cell elastic modulus being observed upon withdrawal of the drug. The results predict that cytoskeletal disrupting drugs may be more potent in advanced stages of glaucoma.
青光眼是一种具有破坏性的神经退行性疾病，可导致视力丧失，并与视网膜神经节细胞的不可逆损伤有关。尽管疾病的发病机制尚不清楚，但我们最近证明，在有青光眼病史的人类供体眼中，眼小梁网（HTM）的硬度会显著增加。在此我们报告，模拟正常和青光眼性HTM顺应性条件的聚丙烯酰胺水凝胶，可深刻调节覆盖的HTM细胞的细胞骨架动力学和弹性模量。基质顺应性还调节HTM细胞对Latrunculin-B（一种目前正在进行治疗青光眼的人体临床试验的细胞骨架破坏剂）的反应。此外，我们观察到Latrunculin-B的顺应性依赖性反弹效应，在药物撤药后观察到HTM细胞弹性模量意外增加。结果预测，细胞骨架破坏药物在青光眼晚期可能更有效。
