The Na-K-Cl cotransporter in the brain edema of acute liver failure
The Na-K-Cl cotransporter in the brain edema of acute liver failure
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DOI：
10.1016/j.jhep.2010.06.041
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发表时间：
2011-02-01
影响因子：
25.7
通讯作者：
Norenberg, Michael D.
中科院分区：
文献类型：
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作者：
Jayakumar, Arumugam R.;Valdes, Vanessa;Norenberg, Michael D.
背景和目标：与颅内压升高相关的星形胶质细胞肿胀和脑水肿是急性肝功能衰竭（ALF）的主要并发症。这种星形胶质细胞肿胀的机制！然而，对脑水肿的认识还不十分清楚。我们最近发现，氨，在ALF的一个关键的病因因素，导致激活的Na-K-Cl协同转运蛋白-1（NKCC 1）在培养的星形胶质细胞，这种激活的抑制导致减少星形胶质细胞肿胀，这表明NKCC 1激活可能是一个重要的因素，在脑水肿的机制在ALF。为了确定NKCC激活是否也参与体内脑水肿，我们研究了NKCC激活是否发生在硫代乙酰胺（TAA）大鼠ALF模型，并确定是否与NKCC抑制剂布美他尼治疗降低TAA治疗rats.Methods的脑水肿的严重程度：脑水含量测定使用重量法。NKCC 1磷酸化和蛋白质表达通过蛋白质印迹法测定。NKCC活性测定大脑皮层slices.Results：NKCC活性升高TAA治疗大鼠的大脑皮层切片相比，假手术动物。蛋白质印迹分析显示，皮质组织中总的以及磷酸化（活化）的NKCC 1蛋白表达显著增加。这些研究结果与一个显着增加脑水含量，这是衰减与NKCC抑制剂bumetanide.Conclusions治疗：我们的研究表明，参与NKCC在实验性ALF脑水肿的发展，并针对NKCC可能是一个有用的治疗策略，在人类ALF。由Elsevier B. V.代表欧洲肝脏研究协会发表。
Background & Aims: Astrocyte swelling and brain edema associated with increased intracranial pressure are major complications of acute liver failure (ALF). The mechanism for such astrocyte swelling! brain edema, however, is not well understood. We recently found that ammonia, a key etiological factor in ALF, caused the activation of the Na-K-Cl cotransporter-1 (NKCC1) in cultured astrocytes, and that inhibition of such activation led to a reduction in astrocyte swelling, suggesting that NKCC1 activation may be an important factor in the mechanism of brain edema in ALF. To determine whether NKCC activation is also involved in brain edema in vivo, we examined whether NKCC activation occurs in the thioacetamide (TAA) rat model of ALF and determined whether treatment with the NKCC inhibitor bumetanide reduces the severity of brain edema in TAA-treated rats.Methods: Brain water content was measured using the gravimetric method. NKCC1 phosphorylation and protein expression were measured by Western blots. NKCC activity was measured in brain cortical slices.Results: NKCC activity was elevated in brain cortical slices of TAA-treated rats as compared to sham animals. Western blot analysis showed significant increases in total as well as phosphorylated (activated) NKCC1 protein expression in the cortical tissue. These findings were associated with a significant increase in brain water content which was attenuated by treatment with the NKCC inhibitor bumetanide.Conclusions: Our studies suggest the involvement of NKCC in the development of brain edema in experimental ALF, and that targeting NKCC may represent a useful therapeutic strategy in humans with ALF. Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.