Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast.
Induction of oxidative and nitrosative damage leads to cerebrovascular inflammation in an animal model of mild traumatic brain injury induced by primary blast.
复制标题
诱导氧化和亚硝化损伤会导致脑血管炎症，这是由原发性爆炸引起的轻度外伤性脑损伤的动物模型。
DOI：
10.1016/j.freeradbiomed.2013.02.029
复制
发表时间：
2013-07
影响因子：
7.4
通讯作者：
Haorah, James
中科院分区：
文献类型：
--
作者：
Abdul-Muneer, P. M.;Schuetz, Heather;Wang, Fang;Skotak, Maciej;Jones, Joselyn;Gorantla, Santhi;Zimmerman, Matthew C.;Chandra, Namas;Haorah, James
关键词：
我们调查的假设，脑血管屏障界面（血脑屏障，BBB）的氧化损伤导致的发展轻度创伤性脑损伤（mTBI）在初级冲击波频谱。这种血管层结构损伤的基本生化和细胞机制的研究在一种新的动物模型的冲击管。我们首先确定，低频（123 kPa）单次或重复冲击波通过暴露后6-24小时发生的急性机械力引起的生化激活引起BBB/脑损伤。脑血管的这种生化损伤是由自由基生成酶NADPH氧化酶（NOX 1）和诱导型一氧化氮合酶（iNOS）的诱导引发的。冲击波暴露诱导这些酶与氧化和亚硝化损伤（4 HNE/3 NT）的特征以及脑微血管中BBB紧密连接（TJ）蛋白闭合蛋白、闭合蛋白-5和zonula occluden 1（ZO-1）的减少密切相关。与TJ蛋白破坏平行，血管周围单位显著减少，通过与动力学曲线一致的单次或重复冲击波暴露。氧化应激诱导的基质金属蛋白酶和流体通道水通道蛋白-4活化介导了血管和血管周围单位的松弛，促进了血管液空化/水肿，增强了BBB的渗漏和神经炎症的进展。在体内模型中通过Na-Fl/EB低分子量示踪剂的渗透性增强和免疫细胞穿过BBB的浸润功能性地证明了BBB渗漏和神经炎症。脑细胞NSE/S100β的检测证实了冲击波脑损伤后神经-星形胶质细胞的损伤。我们的假设，即脑血管损伤发生在轻度TBI神经系统疾病的发展之前，进一步证实了caspase-3的激活和细胞凋亡主要围绕血管周围区域。因此，冲击波诱导氧化应激和MMPs活化是脑血管BBB渗漏和神经炎症的机制之一。
We investigate the hypothesis that oxidative damage of the cerebral vascular barrier interface (the blood brain barrier, BBB) causes the development of mild traumatic brain injury (mTBI) during primary blast wave spectrum. The underlying biochemical and cellular mechanisms of this vascular layer-structure injury are examined in a novel animal model of shock tube. We first established that low frequency (123 kPa) single or repeated shock wave causes BBB/brain injury through biochemical activation by acute mechanical force that occurs at 6–24 hrs after the exposure. This biochemical damage of the cerebral vasculature is initiated by the induction of free radical generating enzymes NADPH oxidase (NOX1) and inducible nitric oxide synthase (iNOS). Induction of these enzymes by shock wave exposure correlated well with the signatures of oxidative and nitrosative damage (4HNE/3NT) and reduction of the BBB tight junction (TJ) proteins occludin, claudin-5 and zonula occluden 1 (ZO-1) in the brain microvessel. In parallel with TJ protein disruption, the perivascular unit was significantly diminished by single or repeated shock wave exposure coinciding with the kinetic profile. Loosening of the vasculature and perivascular unit was mediated by oxidative stress-induced activation of matrix metalloproteinases and fluid channel aquaporin-4, promoting vascular fluid cavitation/edema, enhanced leakiness of the BBB and progression of neuroinflammation. The BBB leakiness and neuroinflammation were functionally demonstrated in an in vivo model by enhanced permeability of Na-Fl/EB low molecular weight tracers and the infiltration of immune cells across the BBB. The detection of brain cell matters NSE/S100β in the blood samples validated the neuro-astroglial injury in shock wave TBI. Our hypothesis that cerebral vascular injury occurring prior to the development of neurological disorders in mild TBI was further confirmed by the activation of caspase-3 and cell apoptosis mostly around the perivascular region. Thus, induction of oxidative stress and MMPs activation by shock wave underlies the mechanisms of cerebral vascular BBB leakage and neuroinflammation.
登录
查看更多内容
影响因子：
4.2
作者：
Sundaramurthy, Aravind;Alai, Aaron;Chandra, Namas
通讯作者：
Chandra, Namas
影响因子：
4.2
作者：
Kamnaksh, Alaa;Kovesdi, Erzsebet;Agoston, Denes V.
通讯作者：
Agoston, Denes V.
影响因子：
4.1
作者：
Berger, RP;Adelson, PD;Kochanek, PM
通讯作者：
Kochanek, PM
影响因子：
3.8
作者：
VandeVord, Pamela J.;Bolander, Richard;Bir, Cynthia A.
通讯作者：
Bir, Cynthia A.
影响因子：
25
作者：
Winkler EA;Bell RD;Zlokovic BV
通讯作者：
Zlokovic BV