Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy
Inhibition of tumor necrosis factor-α improves physiological angiogenesis and reduces pathological neovascularization in ischemic retinopathy
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DOI：
10.1016/s0002-9440(10)62284-5
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发表时间：
2005-02-01
影响因子：
6
通讯作者：
Stitt, AW
中科院分区：
文献类型：
--
作者：
Gardiner, TA;Gibson, DS;Stitt, AW
本研究在氧诱导视网膜病变（OIR）小鼠模型中测试抑制促血管生成炎性细胞因子肿瘤坏死因子(TNF)- α是否可以调节视网膜缺氧和视网膜前新生血管。在出生后第7至12天（P7至P12）暴露于75%氧气的tnf - α -/-和野生型（WT）对照C57B6新生小鼠中产生OIR。每只WT窝中有一半小鼠从P12重新引入室内空气到P17，每天腹腔注射细胞因子抑制剂semapimod（以前称为CNI-1493） （5 mg/kg）。视网膜前新生血管和视网膜内血管重建的程度通过视网膜平支架的图像分析来量化，通过免疫荧光定位低氧敏感药物吡莫硝唑（hypoxyprobe， HP）来量化与血管重建相关的视网膜缺氧。HP加合物也通过Western分析进行了表征，并通过竞争性酶联免疫吸附法进行了定量。tnf - α -/-和WT小鼠在P12时对高氧诱导的视网膜缺血表现出相似的敏感性。在P13时，semapimod治疗的TNFalpha-/-和WT小鼠早期再灌注明显延迟。然而，在P17时，与未治疗的WT小鼠视网膜病变相比，这两组的血管恢复明显更好，视网膜缺血/缺氧和视网膜前新生血管减少。免疫组织化学显示HP沉积在无血管的视网膜内，但未在视网膜前新生血管的基础区域沉积，表明这种异常的血管可以减少视网膜缺氧。抑制tnf - α显著改善缺血组织内的血管恢复，减少OIR的病理性新生血管。HP为实验性缺血性视网膜病变组织缺氧的定位和定量提供了有用的工具。
The present study was undertaken to test whether inhibition of the proangiogenic inflammatory cytokine tumor necrosis factor (TNF)-alpha can modulate retinal hypoxia and preretinal neovascularization in a murine model of oxygen-induced retinopathy (OIR). OIR was produced in TNF-alpha-/- and wild-type (WT) control C57B6 neonatal mice by exposure to 75% oxygen between postnatal days 7 and 12 (P7 to P12). Half of each WT litter was treated with the cytokine inhibitor semapimod (formerly known as CNI-1493) (5 mg/kg) by daily intraperitoneal injection from the time of reintroduction to room air at P12 until P17. The extent of preretinal neovascularization and intraretinal revascularization was quantified by image analysis of retinal flat-mounts and retinal hypoxia correlated with vascularization by immunofluorescent localization of the hypoxia-sensitive drug pimonidazole (hypoxyprobe, HP). HP adducts were also characterized by Western analysis and quantified by competitive enzyme-linked immunosorbent assay. TNF-alpha-/- and WT mice showed a similar sensitivity to hyperoxia-induced retinal ischemia at P12. At P13 some delay in early reperfusion was evident in TNFalpha-/- and WT mice treated with semapimod. However, at P17 both these groups had significantly better vascular recovery with less ischemic/hypoxic retina and preretinal neovascularization compared to untreated retinopathy in WT mice. Immunohistochemistry showed deposition of HP in the avascular inner retina but not in areas underlying preretinal neovascularization, indicating that such aberrant vasculature can reduce retinal hypoxia. Inhibition of TNF-alpha significantly, improves vascular recovery within ischemic tissue and reduces pathological neovascularization in OIR. HP provides a useful tool for mapping and quantifying tissue hypoxia in experimental ischemic retinopathy.