Retinal ischemia and reperfusion causes capillary degeneration: Similarities to diabetes
Retinal ischemia and reperfusion causes capillary degeneration: Similarities to diabetes
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DOI：
10.1167/iovs.06-0510
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发表时间：
2007-01-01
影响因子：
4.4
通讯作者：
Kern, Timothy S.
中科院分区：
文献类型：
--
作者：
Zheng, Ling;Gong, Bendi;Kern, Timothy S.
目的。视网膜神经元与脉管系统在正常情况下相互作用，视网膜脉管系统闭塞可导致视网膜神经元损伤。然而，神经视网膜的损伤是否会损害血管系统尚不清楚。本研究旨在探讨视网膜血管细胞和非血管细胞之间的关系。研究了视网膜血管系统对损伤（缺血和再灌注；I/R）的反应，这种损伤已知会导致神经元变性。通过升高眼内压（IOP）诱导Lewis大鼠和C57BL/6J小鼠视网膜I/R损伤，并立即建立再灌注。部分大鼠术前给予氨基胍（AMG， 50 mg/Kg BW饮水）预处理。Western blot检测聚（adp -核糖）聚合酶（PARP）活性和诱导型一氧化氮合酶（iNOS）、环氧化酶-2 （COX-2）表达，qPCR检测术后2、7 d tnf - α和细胞间粘附分子(ICAM)-1 mRNA水平。在I/R损伤后2和7 d，定量观察视网膜神经细胞凋亡（TUNEL法）、神经节细胞层细胞密度和视网膜厚度，并观察TUNEL阳性毛细血管细胞和变性毛细血管的数量。在I/R损伤后2、5、8、14天，观察C57BL/6J小鼠视网膜神经变性和毛细血管变性。正如预期的那样，大鼠和小鼠模型在I/R损伤后2天视网膜神经节细胞层细胞明显丢失。相比之下，在这两个模型中，视网膜血管系统基本上没有病理变化。令人惊讶的是，损伤后7 ~ 8天，退化的毛细血管数量显著增加。氨基胍显著抑制I/ r诱导的大鼠毛细血管变性和神经变性。视网膜I/R引起大鼠PARP活性增加（通过聚（adp核糖）相关蛋白检测），以及iNOS、COX-2、tnf - α和ICAM-1水平上调，与炎症过程一致。毛细血管变性是急性IOP升高的一个未被识别的组成部分，只有在神经退行性变严重后才会发生。因此，这一发现提出了神经视网膜损伤导致毛细血管变性的可能性。氨基胍是一种非特异性的iNOS抑制剂，可以抑制I/ r诱导的视网膜神经元和血管细胞的变性。建立视网膜缺血再灌注模型将为研究青光眼和糖尿病视网膜病变等疾病中神经元损伤和血管损伤之间的关系提供有用的工具。
PURPOSE. Retinal neurons and vasculature interact with each other under normal conditions, and occlusion of the retinal vasculature can result in damage to retinal neurons. Whether damage to the neural retina will damage the vasculature, however, is less clear. This study was conducted to explore the relationship between vascular and nonvascular cells of the retina. The response of the retinal vasculature to an injury (ischemia and reperfusion; I/R) that is known to cause neuronal degeneration was studied.METHODS. I/R injury to the retinas was induced in Lewis rats and C57BL/6J mice by elevating intraocular pressure (IOP), and reperfusion was established immediately afterward. Some rats were pretreated with aminoguanidine (AMG, 50 mg/Kg BW in drinking water) before the procedure. Poly(ADP-ribose) polymerase (PARP) activity and expression of inducible nitric oxide synthase (iNOS), and cycloxygenase-2 (COX-2) were measured by Western blot analysis, and levels of TNF-alpha and intercellular adhesion molecule (ICAM)-1 mRNA were measured by qPCR at 2 and 7 days after the procedure. Also at 2 and 7 days after the I/R injury, apoptosis of retinal neural cells (demonstrated by TUNEL assay), density of cells in the ganglion cell layer, and thickness of retinas were quantitated, and the number of TUNEL-positive capillary cells and degenerated capillaries were assessed. Retinal neurodegeneration and capillary degeneration were also examined in C57BL/6J mice 2, 5, 8, and 14 days after I/R injury.RESULTS. As expected, loss of cells in the retinal ganglion cell layer was apparent 2 days after I/R injury in the rat and mouse models. In contrast, the retinal vasculature had essentially no pathology at this time in either model. Surprisingly, the number of degenerated capillaries increased greatly by 7 to 8 days after the injury. Administration of aminoguanidine significantly inhibited the I/R-induced capillary degeneration as well as neurodegeneration in the rat model. Retinal I/R caused increased PARP activity (detected by poly(ADP-ribosy) lated proteins), as well as upregulation of iNOS, COX-2, TNF-alpha, and ICAM-1 levels in rats, consistent with an inflammatory process.CONCLUSIONS. Capillary degeneration is an unrecognized component of acutely elevated IOP and develops only after neurodegeneration is severe. Thus, this finding raises the possibility that damage to the neural retina contributes to capillary degeneration. Aminoguanidine, a nonspecific inhibitor of iNOS, inhibited I/R-induced degeneration of both neuronal and vascular cells of the retina. The model of retinal ischemia and reperfusion will be a useful tool for investigating the relationship between neuronal damage and vascular damage in glaucoma and other diseases such as diabetic retinopathy.