Yao Xiaoming, Uchida Kazuyoshi, Papadopoulos Marios C, Zador Zsolt, Manley Geoffrey T, Verkman Alan S
1 Department of Neurological Surgery, University of California , San Francisco, California.
2 Departments of Medicine and Physiology, University of California , San Francisco, California.
J Neurotrauma. 2015 Oct 1;32(19):1458-64. doi: 10.1089/neu.2014.3675. Epub 2015 May 27.
Brain edema following traumatic brain injury (TBI) is associated with considerable morbidity and mortality. Prior indirect evidence has suggested the involvement of astrocyte water channel aquaporin-4 (AQP4) in the pathogenesis of TBI. Here, focal TBI was produced in wild type (AQP4(+/+)) and knockout (AQP4(-/-)) mice by controlled cortical impact injury (CCI) following craniotomy with dura intact (parameters: velocity 4.5 m/sec, depth 1.7 mm, dwell time 150 msec). AQP4-deficient mice showed a small but significant reduction in injury volume in the first week after CCI, with a small improvement in neurological outcome. Mechanistic studies showed reduced intracranial pressure at 6 h after CCI in AQP4(-/-) mice, compared with AQP4(+/+) control mice (11 vs. 19 mm Hg), with reduced local brain water accumulation as assessed gravimetrically. Transmission electron microscopy showed reduced astrocyte foot-process area in AQP4(-/-) mice at 24 h after CCI, with greater capillary lumen area. Blood-brain barrier disruption assessed by Evans blue dye extravasation was similar in AQP4(+/+) and AQP4(-/-) mice. We conclude that the mildly improved outcome in AQP4(-/-) mice following CCI results from reduced cytotoxic brain water accumulation, though concurrent cytotoxic and vasogenic mechanisms in TBI make the differences small compared to those seen in disorders where cytotoxic edema predominates.
创伤性脑损伤（TBI）后的脑水肿与相当高的发病率和死亡率相关。先前的间接证据表明星形胶质细胞水通道水通道蛋白4（AQP4）参与了TBI的发病机制。在此，通过在硬脑膜完整的开颅术后进行控制性皮质撞击伤（CCI），在野生型（AQP4(+/+)）和基因敲除（AQP4(-/-)）小鼠中制造局灶性TBI（参数：速度4.5米/秒，深度1.7毫米，停留时间150毫秒）。AQP4基因缺陷小鼠在CCI后的第一周损伤体积有轻微但显著的减少，神经功能结局有轻微改善。机制研究表明，与AQP4(+/+)对照小鼠相比，AQP4(-/-)小鼠在CCI后6小时颅内压降低（11对19毫米汞柱），通过重量法评估局部脑水积聚减少。透射电子显微镜显示，在CCI后24小时，AQP4(-/-)小鼠的星形胶质细胞足突面积减少，毛细血管腔面积增大。通过伊文思蓝染料外渗评估的血脑屏障破坏在AQP4(+/+)和AQP4(-/-)小鼠中相似。我们得出结论，AQP4(-/-)小鼠在CCI后结局的轻微改善是由于细胞毒性脑水积聚减少，尽管TBI中同时存在细胞毒性和血管源性机制，与细胞毒性水肿占主导的疾病相比，差异较小。
