Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis
Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis
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DOI：
10.1074/jbc.m413627200
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发表时间：
2005-04-08
影响因子：
4.8
通讯作者：
Verkman, AS
中科院分区：
文献类型：
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作者：
Papadopoulos, MC;Verkman, AS
星形胶质细胞水通道蛋白 - 4（AQP4）促进水进出脑实质。为了研究AQP4在脑膜炎诱导的脑水肿中的作用，将肺炎链球菌注射到野生型和AQP4基因敲除小鼠的脑脊液（CSF）中。在30小时时，AQP4缺陷型小鼠的颅内压（9±1对比25±5厘米水柱）和脑水积聚（2±1对比9±1微升）显著降低，并且在60小时时存活率提高（80%对比0%存活率），而脑脊液细菌数和白细胞计数相当。脑膜炎使野生型小鼠的星形胶质细胞足突明显肿胀，但AQP4基因敲除小鼠则没有，并且减缓了惰性大分子在脑细胞外间隙的扩散。在脑膜炎中，AQP4蛋白强烈上调，导致血脑屏障的水通透性（Pf）比未感染的野生型小鼠高约5倍。利用测量的Pf和脑脊液动力学进行的数学建模准确地模拟了脑膜炎引起的颅内压升高和脑水增多，并预测了防止AQP4上调的有益效果。我们的研究结果为急性细菌性脑膜炎脑水肿的发病机制提供了一种新的分子机制，并表明抑制AQP4功能或其上调可能显著改善临床结果。
The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitis-induced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 +/- 1 versus 25 +/- 5 cm H2O) and brain water accumulation (2 +/- 1 versus 9 +/- 1 mu l) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a similar to 5-fold higher water permeability (P-f) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P-f and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 up-regulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.