Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions.
Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions.
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DOI：
10.1371/journal.pone.0056419
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Michalski D
中科院分区：
文献类型：
--
作者：
Krueger M;Härtig W;Reichenbach A;Bechmann I;Michalski D
术语血脑屏障（BBB）涉及脑血管阻止亲水性和大分子进入脑的能力，从而对脑内稳态起关键作用。事实上，内皮紧密连接的实验性打开导致BBB的破坏，例如通过白蛋白渗漏证明。这和类似的观察结果导致的结论是，血脑屏障的崩溃主要是介导的损害紧密连接复合物，但证据超微结构数据是罕见的。由于BBB的功能缺陷导致卒中后出血性转化和脑水肿的风险增加，这两者对临床结果都有重要影响，因此我们使用Wistar大鼠局灶性脑缺血的栓塞模型来研究BBB破裂的机制，以密切模仿基本的人类病理生理学。缺血诱导的血脑屏障击穿检测使用静脉注射的FITC-白蛋白和FITC-白蛋白外渗区域的紧密连接，随后使用荧光和电子显微镜进行了研究。与我们的预期相反，在缺血诱导后25小时，紧密连接复合物的形态（在超微结构上鉴定并使用针对跨细胞蛋白occludin和claudin-5的抗体）似乎在FITC-白蛋白大量泄漏到神经元中的区域中规律地维持。此外，受影响半球中沿泛层粘连蛋白标记的血管的闭塞蛋白信号沿着泛层粘连蛋白标记的血管等于未受影响的对侧（比率：0.966 vs. 0.963; P = 0.500）。 在缺血诱导后5和25小时的额外超微结构分析清楚地表明，血管周围的FITC-白蛋白外渗与完整的紧密连接，而内皮细胞表现出增强的跨内皮囊泡运输和变性的迹象。因此，血脑屏障的破坏和FITC-白蛋白的渗漏不能与单独的常见紧密连接蛋白的染色模式相关。了解导致功能性内皮改变和内皮损伤的机制可能为卒中提供新的保护靶点。
The term blood-brain barrier (BBB) relates to the ability of cerebral vessels to hold back hydrophilic and large molecules from entering the brain, thereby crucially contributing to brain homeostasis. In fact, experimental opening of endothelial tight junctions causes a breakdown of the BBB evidenced as for instance by albumin leakage. This and similar observations led to the conclusion that BBB breakdown is predominantly mediated by damage to tight junction complexes, but evidentiary ultrastructural data are rare. Since functional deficits of the BBB contribute to an increased risk of hemorrhagic transformation and brain edema after stroke, which both critically impact on the clinical outcome, we studied the mechanism of BBB breakdown using an embolic model of focal cerebral ischemia in Wistar rats to closely mimic the essential human pathophysiology. Ischemia-induced BBB breakdown was detected using intravenous injection of FITC-albumin and tight junctions in areas of FITC-albumin extravasation were subsequently studied using fluorescence and electron microscopy. Against our expectation, 25 hours after ischemia induction the morphology of tight junction complexes (identified ultrastructurally and using antibodies against the transcellular proteins occludin and claudin-5) appeared to be regularly maintained in regions where FITC-albumin massively leaked into the neuropil. Furthermore, occludin signals along pan-laminin-labeled vessels in the affected hemisphere equaled the non-affected contralateral side (ratio: 0.966 vs. 0.963; P = 0.500). Additional ultrastructural analyses at 5 and 25 h after ischemia induction clearly indicated FITC-albumin extravasation around vessels with intact tight junctions, while the endothelium exhibited enhanced transendothelial vesicle trafficking and signs of degeneration. Thus, BBB breakdown and leakage of FITC-albumin cannot be correlated with staining patterns for common tight junction proteins alone. Understanding the mechanisms causing functional endothelial alterations and endothelial damage is likely to provide novel protective targets in stroke.
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DOI：
10.1038/jcbfm.2010.97
发表时间：
2011-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
8.3
作者：
Chen B;Friedman B;Cheng Q;Tsai P;Schim E;Kleinfeld D;Lyden PD
通讯作者：
Lyden PD
影响因子：
2.9
作者：
Belayev, L;Busto, R;Ginsberg, MD
通讯作者：
Ginsberg, MD
影响因子：
2.2
作者：
Dente, CJ;Steffes, CP;Tyburski, JG
通讯作者：
Tyburski, JG
影响因子：
8.3
作者：
Fisher M;Feuerstein G;Howells DW;Hurn PD;Kent TA;Savitz SI;Lo EH;STAIR Group
通讯作者：
STAIR Group