Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA.
J Neurosurg. 2010 May;112(5):1095-104. doi: 10.3171/2009.8.JNS081704.
Dysregulation of water homeostasis induces cerebral edema. Edema is a major cause of morbidity and mortality following traumatic brain injury (TBI). Aquaporin-1 (AQP-1), a water channel found in the brain, can function as a transporter for CO2 across the cellular membrane. Additionally, AQP-1's promoter contains a glucocorticoid response element. Thus, AQP-1 may be involved with edema-related brain injury and might be modulated by external conditions such as the pH and the presence of steroids. In this study, the authors investigated the hypotheses that: 1) AQP-1 participates in brain water homeostasis following TBI; 2) secondary injury (for example, acidosis) alters the expression of AQP-1 and exacerbates cerebral edema; and 3) corticosteroids augment brain AQP-1 expression and differentially affect cerebral edema under nonacidotic and acidotic conditions.
Anesthetized Sprague-Dawley rats were subjected to moderate to severe TBI (2.5-3.5 atm) or surgery without injury, and they were randomized to receive a 3-mg/kg bolus of intravenous dexamethasone within 10 minutes after injury or surgery, a 3-mg/kg bolus of dexamethasone followed by 1-mg/kg maintenance doses every 8 hours for 24 hours, or saline boluses at similar time intervals. A second group of animals was subjected to respiratory acidosis with target arterial blood pH 6.8-7.2 for 1 hour following the surgery or injury. To evaluate selective blockage of AQP-1, some animals received a single intraperitoneal dose of HgCl2 (0.3-30.0 mmol/L) within 30 minutes of injury or surgery. At 4 or 24 hours postinjury, animals were killed and their brains were harvested for mRNA, protein, or water content analyses.
The authors demonstrated elevated cerebral edema levels at 4 and 24 hours following TBI. Dexamethasone administration within 1 hour of TBI attenuated the cerebral edema under nonacidotic conditions but worsened it under acidotic conditions. Selective blockage of AQP-1 channels with HgCl2 attenuated the edematous effects of corticosteroids and acidosis. Reverse transcriptase polymerase chain reaction and immunohistochemical analyses demonstrated a paucity of AQP-1 in the cerebral cortices of the uninjured animals. In contrast, AQP-1 mRNA and protein levels were higher in the cerebral cortices of animals that sustained a TBI.
These findings implicate an important, modifiable role for AQP-1 in water homeostasis within the CNS following TBI.
水稳态失调会引起脑水肿。脑水肿是创伤性脑损伤（TBI）后发病率和死亡率的主要原因。水通道蛋白-1（AQP-1）是一种在大脑中发现的水通道，可作为跨细胞膜的 CO2 转运蛋白。此外，AQP-1 的启动子包含糖皮质激素反应元件。因此，AQP-1 可能与水肿相关的脑损伤有关，并且可能受到外部条件（例如 pH 值和类固醇的存在）的调节。在这项研究中，作者提出了以下假设：1）AQP-1 参与 TBI 后的脑水稳态；2）继发性损伤（例如酸中毒）改变 AQP-1 的表达并加重脑水肿；3）皮质类固醇可增加脑 AQP-1 的表达，并在非酸中毒和酸中毒条件下对脑水肿产生不同的影响。
麻醉的 Sprague-Dawley 大鼠接受中度至重度 TBI（2.5-3.5 大气压）或无损伤手术，并在损伤后 10 分钟内随机接受静脉内地塞米松 3mg/kg 推注，或地塞米松 3mg/kg 推注后 8 小时每小时维持剂量 1mg/kg ，共 24 小时，或在相似的时间间隔内给予盐水推注。第二组动物在手术后或损伤后 1 小时进行呼吸性酸中毒，目标动脉血 pH 值为 6.8-7.2。为了评估 AQP-1 的选择性阻断，一些动物在损伤或手术后 30 分钟内接受单次腹腔内 HgCl2（0.3-30.0mmol/L）剂量。在损伤后 4 或 24 小时，处死动物并采集其大脑进行 mRNA、蛋白质或水含量分析。
作者发现在 TBI 后 4 和 24 小时脑水肿水平升高。TBI 后 1 小时内给予地塞米松可在非酸中毒条件下减轻脑水肿，但在酸中毒条件下加重脑水肿。用 HgCl2 选择性阻断 AQP-1 通道可减轻皮质类固醇和酸中毒的水肿作用。逆转录聚合酶链反应和免疫组织化学分析显示，未受伤动物的大脑皮质中 AQP-1 含量较少。相反，在发生 TBI 的动物的大脑皮质中，AQP-1mRNA 和蛋白质水平更高。
这些发现表明，AQP-1 在 TBI 后中枢神经系统内的水稳态中具有重要的、可调节的作用。
