Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells.
Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells.
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发表时间：
2000
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通讯作者：
G. Tezel;M. Wax
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作者：
G. Tezel;M. Wax
虽然视神经乳头中的胶质细胞在青光眼中经历再活化过程，但胶质细胞在视网膜神经节细胞的青光眼性神经变性中的作用尚不清楚。使用共培养系统，其中视网膜神经节细胞和神经胶质细胞生长在不同的层，但共享相同的培养基，我们研究了神经胶质细胞对视网膜神经节细胞的存活后，暴露于不同的应激条件下，典型的模拟缺血和静水压力升高。暴露于这些应激因素后，我们观察到神经胶质细胞分泌肿瘤坏死因子-α（TNF-α）以及其他有害物质，如一氧化氮进入共培养介质，并促进视网膜神经节细胞的凋亡死亡，通过形态学，末端脱氧核苷酸转移酶介导的dUTP缺口末端标记和caspase活性评估。被动转移实验证实了这些有害作用的胶质起源。此外，视网膜神经节细胞凋亡被TNF-α中和抗体减弱约66%，诱导型一氧化氮合酶选择性抑制剂（1400 W）减弱约50%。由于眼内压升高和局部缺血是青光眼患者眼睛中发现的两个突出的应激因素，这些发现揭示了青光眼视网膜神经节细胞死亡的一种新的胶质细胞启动的致病机制。此外，这些研究结果表明，抑制由再活化的胶质细胞释放的TNF-α可能为治疗青光眼性视神经病变的神经保护提供新的治疗靶点。
Although glial cells in the optic nerve head undergo a reactivation process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a coculture system in which retinal ganglion cells and glial cells are grown on different layers but share the same culture medium, we studied the influences of glial cells on survival of retinal ganglion cells after exposure to different stress conditions typified by simulated ischemia and elevated hydrostatic pressure. After the exposure to these stressors, we observed that glial cells secreted tumor necrosis factor-alpha (TNF-alpha) as well as other noxious agents such as nitric oxide into the coculture media and facilitated the apoptotic death of retinal ganglion cells as assessed by morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase activity. The glial origin of these noxious effects was confirmed by passive transfer experiments. Furthermore, retinal ganglion cell apoptosis was attenuated approximately 66% by a neutralizing antibody against TNF-alpha and 50% by a selective inhibitor of inducible nitric oxide synthase (1400W). Because elevated intraocular pressure and ischemia are two prominent stress factors identified in the eyes of patients with glaucoma, these findings reveal a novel glia-initiated pathogenic mechanism for retinal ganglion cell death in glaucoma. In addition, these findings suggest that the inhibition of TNF-alpha that is released by reactivated glial cells may provide a novel therapeutic target for neuroprotection in the treatment of glaucomatous optic neuropathy.