Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model
Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model
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DOI：
10.1167/iovs.07-1356
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发表时间：
2008-04-01
影响因子：
4.4
通讯作者：
Hartnett, M. Elizabeth
中科院分区：
文献类型：
--
作者：
Saito, Yuta;Uppal, Abhineet;Hartnett, M. Elizabeth
目的。研究NAD(P) H氧化酶依赖的氧应激后的结果，这些结果与今天早产儿所经历的相似，使用大鼠早产儿视网膜病变模型。在出生4小时内，幼崽及其母亲每天循环50%至10%的氧气，持续14天，然后返回室内空气（21% O-2, 50/10氧致视网膜病变[OIR]）或补充氧气（28% O-2, 50/10 OIR + SO） 4天。出生后12 ~ 17天腹腔注射特异性NAD(P) H氧化酶抑制剂罗布麻碱（10 mg/kg/d）或PBS，部分幼鼠在杀死前腹腔注射低氧探针。在神经感觉视网膜中测定玻璃体内新生血管（IVNV）、无血管/总视网膜面积、血管内皮生长因子（VEGF）、NAD(P) H氧化酶活性或缺氧视网膜（共轭低氧探针）。将经罗布麻苷处理或对照的人视网膜微血管内皮细胞（RMVECs）暴露于1%或21%的O-2中，检测磷酸化（p-） Janus激酶（JNK）和NAD(p) H氧化酶的活性。与50/10 OIR相比，50/10 OIR + SO的视网膜NAD(P) H氧化酶活性升高，VEGF降低。罗布麻素治疗减少了50/10 OIR + SO的IVNV面积和缺氧视网膜。与暴露于室内空气的RMVECs相比，1% O-2处理的RMVECs的p- JNK增加。不同的氧胁迫会不同程度地激活NAD(P) H氧化酶，从而触发不同的途径（血管生成或细胞凋亡）。本研究中使用的氧应激和结果与人类ROP有关，并可能解释由氧暴露引起的ROP病理生理学的一些复杂性。
PURPOSE. To study NAD( P) H oxidase- dependent outcomes after oxygen stresses that are similar to those experienced by pre-term infants today using a rat model of retinopathy of prematurity.METHODS. Within 4 hours of birth, pups and their mothers were cycled between 50% and 10% oxygen daily for 14 days and were returned to room air ( 21% O-2, 50/10 oxygen-induced retinopathy [ OIR]) or supplemental oxygen ( 28% O-2, 50/10 OIR + SO) for 4 days. Pups received intraperitoneal injections of the specific NAD( P) H oxidase inhibitor apocynin ( 10 mg/kg/d) or of PBS from postnatal day ( P) 12 to P17, and some received intraperitoneal injections of hypoxyprobe before kill. Intravitreous neovascularization ( IVNV), avascular/total retinal areas, vascular endothelial growth factor ( VEGF), NAD( P) H oxidase activity, or hypoxic retina ( conjugated hypoxyprobe) were determined in neurosensory retinas. Human retinal microvascular endothelial cells ( RMVECs) treated with apocynin or control were exposed to 1% or 21% O-2 and assayed for phosphorylated (p-) Janus kinase ( JNK) and NAD( P) H oxidase activity.RESULTS. Retinas from 50/10 OIR + SO had increased NAD( P) H oxidase activity and lower VEGF than did retinas from 50/10 OIR. Apocynin treatment reduced the IVNV area and hypoxic retina in 50/10 OIR + SO. RMVECs treated with 1% O-2 had increased p- JNK compared with RMVECs exposed to room air.CONCLUSIONS. Different oxygen stresses activate NAD( P) H oxidase to varying degrees to trigger disparate pathways ( angiogenesis or apoptosis). The oxygen stresses and outcomes used in this study are relevant to human ROP and may explain some of the complexity in the pathophysiology of ROP resulting from oxygen exposure.