title: Aquaporin-1-mediated cerebral edema following traumatic brain injury: effects of acidosis and corticosteroid administration.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These findings implicate an important, modifiable role for AQP-1 in water homeostasis within the CNS following TBI.
authors.affiliation: Department of Neurosurgery, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA. namdtran@alumni.usc.edu
authors.forename: Nam D
authors.initials: ND
authors.lastname: Tran
authors.forename: Stefan
authors.initials: S
authors.lastname: Kim
authors.forename: Heather K
authors.initials: HK
authors.lastname: Vincent
authors.forename: Anthony
authors.initials: A
authors.lastname: Rodriguez
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: M Ross
authors.initials: MR
authors.lastname: Bullock
authors.forename: Harold F
authors.initials: HF
authors.lastname: Young
mesh_terms: D000138:Acidosis / Q000175:diagnosis* / Q000209:etiology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D051398:Aquaporin 1 / Q000235:genetics*; D015153:Blotting, Western; D001929:Brain Edema / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D001930:Brain Injuries / Q000150:complications*; D017931:DNA Primers / Q000235:genetics; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000893:Anti-Inflammatory Agents; D017931:DNA Primers; D051398:Aquaporin 1; D003907:Dexamethasone