title: Creating a prosurvival phenotype through a histone deacetylase inhibitor in a lethal two-hit model.
abstract: OBJECTIVE
  Hemorrhagic shock (HS) can initiate an exaggerated systemic inflammatory response and multiple organ failure, especially if followed by a subsequent inflammatory insult ("second hit"). We have recently shown that histone deacetylase inhibitors can improve survival in rodent models of HS or septic shock, individually. In the present study, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, could prolong survival in a rodent "two-hit" model: HS followed by septic shock from cecal ligation and puncture (CLP).
  
  
  METHODS
  Male Sprague-Dawley rats (250-300 g) were subjected to sublethal HS (40% blood loss) and then randomly divided into two groups (n = 7/group): VPA and control. The VPA group was treated intraperitoneally with VPA (300 mg/kg in normal saline [NS], volume = 750 μL/kg). The control group was injected with 750 μL/kg NS. After 24 h, all rats received CLP followed immediately by injection of the same dose of VPA (VPA group) or NS (vehicle group). Survival was monitored for 10 days. In a parallel study, serum and peritoneal irrigation fluid from VPA- or vehicle-treated rats were collected 3, 6, and 24 h after CLP, and enzyme-linked immunosorbent assay was performed to analyze myeloperoxidase activity and determine tumor necrosis factor α and interleukin 6 concentrations. Hematoxylin-eosin staining of lungs at 24-h time point was performed to investigate the grade of acute lung injury.
  
  
  RESULTS
  Rats treated with VPA (300 mg/kg) showed significantly higher survival rates (85.7%) compared with the control (14.3%). Moreover, VPA significantly suppressed myeloperoxidase activity (marker of neutrophil-mediated oxidative damage) and inhibited levels of proinflammatory cytokine tumor necrosis factor α and interleukin 6 in the serum and peritoneal cavity. Meanwhile, the severity of acute lung injury was significantly reduced in VPA-treated animals.
  
  
  CONCLUSIONS
  We have demonstrated that VPA treatment improves survival and attenuates inflammation in a rodent two-hit model.
authors.affiliation: *Department of Surgery, Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; †Department of Hepatobiliary Surgery, Xijing Hospital, the Fourth Military Medical University, Xi'an; and ‡Emergency Department, the First Hospital, China Medical University, Shenyang, China; §Department of Pathology, Loyola University Medical Center, Maywood, Illinois; and ∥Department of Surgery, University of Michigan, Ann Arbor, Michigan.
authors.forename: Zhengcai
authors.initials: Z
authors.lastname: Liu
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Chong
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Deperalta
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Duan
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Ihab
authors.initials: I
authors.lastname: Halaweish
authors.forename: Peter
authors.initials: P
authors.lastname: Zhou
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D001202:Ascitic Fluid / Q000201:enzymology; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D008297:Male; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000401:mortality; D012772:Shock, Septic / Q000188:drug therapy* / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*; D000093242:Interleukin-6 Inhibitors
chemical_list: D056572:Histone Deacetylase Inhibitors; D009195:Peroxidase; D014409:Tumor Necrosis Factor-alpha; D014635:Valproic Acid; D000093242:Interleukin-6 Inhibitors