Deleterious role of TNF-α in retinal ischemia-reperfusion injury
Deleterious role of TNF-α in retinal ischemia-reperfusion injury
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DOI：
10.1167/iovs.07-0817
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Rosenbaum, Daniel M.
中科院分区：
文献类型：
--
作者：
Berger, Samuel;Savitz, Sean I.;Rosenbaum, Daniel M.
目的.肿瘤坏死因子（TNF）-α是缺血再灌注损伤中神经元细胞死亡和存活的介导物。本研究通过观察TNF-α及其受体对视网膜组织病理学和功能的影响，进一步阐明TNF-α及其受体在视网膜缺血再灌注损伤中的作用。采用高眼压法对p55和p75基因敲除（KO）小鼠和Sprague-Dawley大鼠进行视网膜缺血再灌注损伤。免疫组化染色确定TNF-α的时间表达。单独的大鼠接受玻璃体内重组TNF-α或中和抗体缺血前或后。进行TUNEL标记以评估细胞死亡，并进行视网膜电图以评估功能。TNF-α表达在缺血再灌注损伤后12 ~ 24小时达到高峰。玻璃体内注射TNF-α抗体后，TUNEL染色减弱。两种转基因科斯都表现出明显更少的功能障碍。缺血后48小时接受重组TNF-α的大鼠表现出夸大的功能障碍。在缺血前用TNF-α抗体治疗的动物显示出显著的功能改善。在视网膜损伤的体内模型中，TNF-α在缺血再灌注损伤中发挥着很大的有害作用。这种细胞因子的直接中和部分保留了视网膜功能。TNF-α的不同特征部分归因于其在损伤后表达的时间。肿瘤坏死因子-α受体的表达和功能，沿着靶向死亡受体介导的细胞凋亡的联合治疗，应进一步探索开发急性视网膜缺血性疾病的神经保护性治疗策略。
PURPOSE. Tumor necrosis factor (TNF)-alpha is a mediator of neuronal cell death and survival in ischemia-reperfusion injury. This study was conducted to further elucidate the role of TNF-alpha and its receptor in an in vivo model of retinal ischemia reperfusion injury by investigating its effects on retinal histopathology and function.METHODS. Retinal ischemia-reperfusion injury was performed on p55 and p75 knockout (KO) mice and Sprague-Dawley rats using the high intraocular pressure method. The temporal expression of TNF-alpha was ascertained with immunohistochemical staining. Separate rats received intravitreal recombinant TNF-alpha or neutralizing antibody before or after ischemia. TUNEL labeling was performed to assess for cell death, and electroretinography was performed to assess function.RESULTS. TNF-alpha expression peaked at 12 to 24 hours after ischemia-reperfusion injury. TUNEL staining was diminished after intravitreal TNF-alpha antibody. Both transgenic KOs demonstrated significantly less functional impairment. Rats receiving recombinant TNF-alpha 48 hours after ischemia showed exaggerated functional impairment. Animals treated with TNF-alpha antibody before ischemia displayed significant functional improvement.CONCLUSIONS. TNF-alpha plays a largely deleterious role in ischemia -reperfusion injury in an in vivo model of retinal injury. Direct neutralization of this cytokine partially preserves retinal function. The diverse characteristics of TNF-alpha are attributed in part to the timing of its expression after injury. TNF-alpha receptor expression and function, along with combination treatments targeting death receptor-mediated apoptosis, should be further explored to develop neuroprotective therapeutic strategies for acute retinal ischemic disorders.