常压高氧可降低大鼠和急性缺血性中风患者血液中的闭合蛋白片段水平。
Normobaric Hyperoxia Reduces Blood Occludin Fragments in Rats and Patients With Acute Ischemic Stroke.
作者信息
Shi Shuhai, Qi Zhifeng, Ma Qingfeng, Pan Rong, Timmins Graham S, Zhao Yongmei, Shi Wenjuan, Zhang Yunzhou, Ji Xunming, Liu Ke Jian
机构信息
From the Cerebrovascular Diseases Research Institute (S.S., Z.Q., Y. Zhao, W.S., X.J., K.J.L.), Department of Neurology (Z.Q., Q.M., Y. Zhang), and Beijing Key Laboratory of Hypoxic Conditioning Translational Medicine (X.J.), Xuanwu Hospital of Capital Medical University, Beijing, China; Department of Neurology, First Affiliated Hospital of Baotou Medical College, Inner Mongolia Autonomous Region, China (S.S.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM (R.P., G.S.T., K.J.L.).
出版信息
Stroke. 2017 Oct;48(10):2848-2854. doi: 10.1161/STROKEAHA.117.017713. Epub 2017 Sep 20.
BACKGROUND AND PURPOSE
Damage of the blood-brain barrier (BBB) increases the incidence of neurovascular complications, especially for cerebral hemorrhage after tPA (tissue-type plasminogen activator) therapy. Currently, there is no effective method to evaluate the extent of BBB damage to guide tPA use. Herein, we investigated whether blood levels of tight junction proteins could serve as biomarker of BBB damages in acute ischemic stroke (AIS) in both rats and patients. We examined whether this biomarker could reflect the extent of BBB permeability during cerebral ischemia/reperfusion and the effects of normobaric hyperoxia (NBO) on BBB damage.
METHODS
Rats were exposed to NBO (100% O) or normoxia (21% O) during middle cerebral artery occlusion. BBB permeability was determined. Occludin and claudin-5 in blood and cerebromicrovessels were measured. Patients with AIS were assigned to oxygen therapy or room air for 4 hours, and blood occludin and claudin-5 were measured at different time points after stroke.
RESULTS
Cerebral ischemia/reperfusion resulted in the degradation of occludin and claudin-5 in microvessels, leading to increased BBB permeability in rats. In blood samples, occludin increased with 4-hour ischemia and remained elevated during reperfusion, correlating well with its loss from ischemic cerebral microvessels. NBO treatment both prevented occludin degradation in microvessels and reduced occludin levels in blood, leading to improved neurological functions in rats. In patients with AIS receiving intravenous tPA thrombolysis, the blood occludin was already elevated when patients arrived at hospital (within 4.5 hours since symptoms appeared) and remained at a high level for 72 hours. NBO significantly lowered the level of blood occludin and improved neurological functions in patients with AIS.
CONCLUSIONS
Blood occludin may be a clinically viable biomarker for evaluating BBB damage during ischemia/reperfusion. NBO therapy has the potential to reduce blood occludin, protect BBB, and improve outcome in AIS patients with intravenous tPA thrombolysis.
CLINICAL TRIAL REGISTRATION
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02974283.
背景与目的
血脑屏障（BBB）受损会增加神经血管并发症的发生率，尤其是在组织型纤溶酶原激活剂（tPA）治疗后发生脑出血的情况。目前，尚无有效的方法来评估BBB损伤程度以指导tPA的使用。在此，我们研究了紧密连接蛋白的血液水平是否可作为大鼠和患者急性缺血性卒中（AIS）中BBB损伤的生物标志物。我们还研究了该生物标志物是否能反映脑缺血/再灌注期间BBB的通透性程度以及常压高氧（NBO）对BBB损伤的影响。
方法
在大脑中动脉闭塞期间，将大鼠暴露于NBO（100%氧气）或常氧（21%氧气）环境中。测定BBB通透性。检测血液和脑微血管中的闭合蛋白和Claudin-5。将AIS患者分为接受氧疗或室内空气治疗4小时组，并在卒中后的不同时间点检测血液中的闭合蛋白和Claudin-5。
结果
脑缺血/再灌注导致微血管中闭合蛋白和Claudin-5降解，导致大鼠BBB通透性增加。在血液样本中，闭合蛋白在缺血4小时时增加，并在再灌注期间保持升高，这与其从缺血性脑微血管中的丢失密切相关。NBO治疗既能防止微血管中闭合蛋白的降解，又能降低血液中闭合蛋白的水平，从而改善大鼠的神经功能。在接受静脉tPA溶栓治疗的AIS患者中，患者入院时（症状出现后4.5小时内）血液中的闭合蛋白就已经升高，并在72小时内保持在高水平。NBO显著降低了AIS患者血液中闭合蛋白的水平，并改善了神经功能。
结论
血液中的闭合蛋白可能是评估缺血/再灌注期间BBB损伤的一种临床上可行的生物标志物。NBO治疗有可能降低血液中的闭合蛋白水平，保护BBB，并改善接受静脉tPA溶栓治疗的AIS患者的预后。
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