Relationship between AQP4 expression and structural damage to the blood-brain barrier at early stages of traumatic brain injury in rats
Relationship between AQP4 expression and structural damage to the blood-brain barrier at early stages of traumatic brain injury in rats
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DOI：
10.3760/cma.j.issn.0366-6999.20131139
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发表时间：
2013-11-20
影响因子：
6.1
通讯作者：
He Zhan-ping
中科院分区：
文献类型：
--
作者：
Lu Hong;Lei Xiao-yan;He Zhan-ping
背景虽然有研究报道水通道蛋白-4 （AQP4）在创伤性脑损伤（TBI）后脑水肿中起重要作用，但对AQP4在TBI早期的表达情况以及血脑屏障结构损伤与血管性水肿的相关性了解甚少。本项目旨在探讨AQP4表达与脑外伤早期血脑屏障损伤的关系。方法120只健康成年Wistar大鼠随机分为假手术组和脑外伤组。TBI组根据不同的时间间隔分为5个亚组：1、3、6、12、24小时。在脑外伤后的不同时间点取出动物的大脑，测量脑含水量。采用光学显微镜（OM）和透射电镜（TEM）观察脑水肿和血脑屏障结构变化，免疫组织化学和Western blotting检测损伤脑组织IgG含量和AQP4蛋白表达。采用SPSS 13.0统计软件对数据进行分析。结果SO组组织IgG阴性，脑组织含水量及AQP4表达未见异常。在TBI组，脑含水量在损伤后6小时显著增加，并在损伤后24小时达到峰值。损伤后1 ~ 6小时，IgG表达量显著升高，24小时仍保持较高水平。病理观察显示伤后1小时血脑屏障损伤。1小时出现血管内皮，逐渐加重，6小时明显。3小时发生细胞内水肿，出现大胶质细胞体和线粒体肿胀。这些现象随着时间的推移而加剧，并在12小时时变得明显。此外，24小时可见小胶质细胞增殖。AQP4蛋白表达在1 h时降低，6 h时最低，12 h时开始升高，呈v型曲线。结论以血脑屏障损伤为特征的血管树突是早期外伤性脑水肿的主要类型。其次是混合性脑水肿，包括血管性水肿和细胞性水肿，随时间加重。AQP4在血管性水肿发作时表达下调，而在细胞内水肿发作时表达上调。
Background Although some studies have reported that aquaporin-4 (AQP4) plays an important role in the brain edema after traumatic brain injury (TBI), little is known about the AQP4 expression in the early stage of TBI, or about the correlation between the structural damage to the blood-brain barrier (BBB) and angioedema. The aim of this project was to investigate the relationship between AQP4 expression and damage to the BBB at early stages of TBI.Methods One hundred and twenty healthy adult Wistar rats were randomly divided into two groups: sham operation group (SO) and TBI group. The TBI group was divided into five sub-groups according to the different time intervals: 1, 3, 6, 12, and 24 hours. The brains of the animals were taken out at different time points after TBI to measure brain water content. The cerebral edema and BBB changes in structure were examined with an optical microscopy (OM) and transmission electron microscopy (TEM), and the IgG content and AQP4 protein expression in traumatic brain tissue were determined by means of immunohistochemistry and Western blotting. The data were analyzed with SPSS 13.0 statistical software.Results In the SO group, tissue was negative for IgG, and there were no abnormalities in brain water content or AQP4 expression. In the TBI group, brain water content significantly increased at 6 hours and peaked at 24 hours following injury. IgG expression significantly increased from 1 to 6 hours following injury, and remained at a high level at 24 hours. Pathological observation revealed BBB damage at 1 hour following injury. Angioedenna appeared at 1 hour, was gradually aggravated, and became obvious at 6 hours. Intracellular edema occurred at 3 hours, with the presence of large glial cell bodies and mitochondrial swelling. These phenomena were aggravated with time and became obvious at 12 hours. In addition, microglial proliferation was visible at 24 hours. AQP4 protein expression were reduced at 1 hour, lowest at 6 hours, and began to increase at 12 hours, showing a V-shaped curve.Conclusions The angioedenna characterized by BBB damage was the primary type of early traumatic brain edema. It was followed by mixed cerebral edema that consisted of angioedema and cellular edema and was aggravated with time. AQP4 expression was down-regulated during the angioedema attack, but AQP4 expression was upregulated during intracellular edema.