title: Beneficial effects of histone deacetylase inhibition with severe hemorrhage and ischemia-reperfusion injury.
abstract: BACKGROUND
  Valproic acid (VPA) is a histone deacetylase inhibitor that may decrease cellular metabolic needs following traumatic injury. We hypothesized that VPA may have beneficial effects in preventing or reducing the cellular and metabolic sequelae of ischemia-reperfusion injury.
  
  
  METHODS
  Twenty-eight Yorkshire swine underwent 35% blood volume hemorrhage, followed by a lethal truncal ischemia-reperfusion injury and 6 h of resuscitation. Physiologic and laboratory parameters were closely measured and the pigs divided into four groups: sham, control (injury protocol), VPA dosing before cross-clamp (VPA-B), and VPA dosing after cross-clamp (VPA-A).
  
  
  RESULTS
  All animals developed significant coagulopathy, acidosis, and anemia. Animals receiving VPA-A had decreased acidosis and coagulopathy as measured by pH (P = 0.016) and international normalized ratio (P = 0.013) over the resuscitation. VPA-A pigs had a decreased requirement for crystalloid (P = 0.007) and epinephrine (P < 0.0001) during resuscitation. Pathologic analysis demonstrated decreased liver injury with VPA administration. VPA administration increased levels of acetylated proteins in liver and lung tissues, and was associated with increased expression of heat shock protein 70 versus controls.
  
  
  CONCLUSIONS
  Valproic acid conferred a significant cardiovascular, metabolic, and pathologic protective effect in a model of severe injury. Earlier administration (VPA-B) was significantly less effective compared with dosing after initial hemorrhage control.
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Washington 98431, USA.
authors.forename: Marlin Wayne
authors.initials: MW
authors.lastname: Causey
authors.forename: Seth
authors.initials: S
authors.lastname: Miller
authors.forename: Zachary
authors.initials: Z
authors.lastname: Hoffer
authors.forename: James
authors.initials: J
authors.lastname: Hempel
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Hasan
authors.initials: H
authors.lastname: Alam
authors.forename: Matthew
authors.initials: M
authors.lastname: Martin
mesh_terms: D000138:Acidosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D004837:Epinephrine / Q000494:pharmacology; D006470:Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000098:blood supply / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000473:pathology; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012151:Resuscitation / Q000379:methods; D034421:Sus scrofa; D015599:Trauma Severity Indices; D014635:Valproic Acid / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014947:Wounds and Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D056572:Histone Deacetylase Inhibitors; D014662:Vasoconstrictor Agents; D014635:Valproic Acid; D004837:Epinephrine
keywords: Hemorrhagic shock; Histone deacetylase; Ischemia; Reperfusion; Valproic acid