Blood-brain barrier breakdown and repair by Src after thrombin-induced injury.
Blood-brain barrier breakdown and repair by Src after thrombin-induced injury.
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DOI：
10.1002/ana.21924
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发表时间：
2010-04
影响因子：
11.2
通讯作者：
Sharp, Frank R.
中科院分区：
文献类型：
--
作者：
Liu, Da-Zhi;Ander, Bradley P.;Xu, Huichun;Shen, Yan;Kaur, Pali;Deng, Wenbin;Sharp, Frank R.
凝血酶介导脑出血后发生的危及生命的脑水肿。因此，我们研究了凝血酶诱导的血脑屏障（BBB）损伤的机制和随后的BBB修复机制。脑室内（i. c. v.）注射凝血酶（20 U）建立大鼠脑室出血模型。凝血酶降低脑微血管内皮细胞（BMVEC）和血管周围星形胶质细胞免疫反应性-表明细胞损伤或死亡;并且，功能性地破坏BBB，如24小时后通过增加的水含量和荧光素钠和伊文思蓝染料的外渗所测量的。注射凝血酶后立即给予非特异性src家族激酶抑制剂PP 2可阻断脑水肿和BBB破坏。凝血酶注射后7 ~ 14天，当血脑屏障通透性和脑含水量恢复时，在脑血管周围观察到新生的内皮细胞和星形胶质细胞。在凝血酶注射后第2天至第6天延迟给予PP 2阻止了水肿和异常BBB渗透性的消退。凝血酶，通过其PAR受体，被假定为激活src激酶磷酸化的分子，急性损伤血脑屏障和产生水肿。因此，src拮抗剂的急性给药阻断水肿。相反，假设在凝血酶注射后src阻断2-6天以防止水肿和异常BBB渗透性的消退，部分原因是src激酶原癌基因成员刺激修复受损BBB的“神经血管龛”中新生BMVEC和血管周围星形胶质细胞的增殖。因此，src激酶不仅介导急性BBB损伤，而且还介导凝血酶诱导的损伤后的慢性BBB修复。
Thrombin mediates the life-threatening cerebral edema that occurs following intracerebral hemorrhage. Therefore, we examined the mechanisms of thrombin-induced injury to the blood-brain barrier (BBB) and subsequent mechanisms of BBB repair. Intracerebroventricular (i.c.v.) injection of thrombin (20 U) was used to model intraventricular hemorrhage in adult rats. Thrombin reduced brain microvascular endothelial cell (BMVEC) and peri-vascular astrocyte immunoreactivity –indicating either cell injury or death; and, functionally disrupted the BBB as measured by increased water content and extravasation of sodium fluorescein and Evans blue dyes 24h later. Administration of non-specific src family kinase inhibitor PP2 immediately following thrombin injections blocked brain edema and BBB disruption. At 7 to 14 days after thrombin injections newborn endothelial cells and astrocytes were observed around cerebral vessels at the time when BBB permeability and cerebral water content resolved. Delayed administration of PP2 on days 2 through 6 following thrombin injections prevented resolution of the edema and abnormal BBB permeability. Thrombin, via its PAR receptors, is postulated to activate src kinase phosphorylation of molecules that acutely injure the BBB and produce edema. Thus, acute administration of src antagonists blocks edema. In contrast, src blockade for 2-6 days following thrombin injections is postulated to prevent resolution of edema and abnormal BBB permeability in part because src kinase proto-oncogene members stimulate proliferation of newborn BMVECs and peri-vascular astrocytes in the “neurovascular niche” that repair the damaged BBB. Thus, src kinases not only mediate acute BBB injury but also mediate chronic BBB repair after thrombin-induced injury.
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