title: Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion.
abstract: OBJECTIVE
  Acute lung injury (ALI) can develop during the course of many clinical conditions, and is associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R.
  
  
  METHODS
  Two experiments were performed. Experiment I: Male Sprague-Dawley rats (250-300 g) were subjected to intestinal ischemia (1h) and reperfusion (3h). They were randomized into 2 groups (n=7 per group) 3 min after ischemia: Vehicle (Veh) and VPA (300 mg/kg, IV). Primary end-point for this study was survival over 4h from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3h (1h ischemia+2h reperfusion) after intestinal I/R injury (Veh vs. VPA, n=9 per group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage.
  
  
  RESULTS
  In Experiment I, 4-h survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p=0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4 ± 0.3 vs. 5.3 ± 0.6, p=0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952 ± 213 pg/ml vs. 7709 ± 1990 pg/ml, p=0.011), and lung tissue concentrations of CINC (1188 ± 28 pg/ml vs. 1298 ± 27 pg/ml, p<0.05), MPO activity (368 ± 23 ng/ml vs. 490 ± 29 ng/ml, p<0.05) and 8-isoprostane levels (1495 ± 221 pg/ml vs. 2191 ± 177 pg/ml, p<0.05).
  
  
  CONCLUSIONS
  VPA treatment improves survival and attenuates ALI in a rat model of intestinal I/R injury, at least in part, through its anti-oxidant and anti-inflammatory effects.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Kyuseok
authors.initials: K
authors.lastname: Kim
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Wei
authors.initials: W
authors.lastname: Chong
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: Kyoungbun
authors.initials: K
authors.lastname: Lee
authors.forename: Marc
authors.initials: M
authors.lastname: Demoya
authors.forename: George C
authors.initials: GC
authors.lastname: Velmahos
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005500:Follow-Up Studies; D007422:Intestines / Q000098:blood supply; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications*; D016896:Treatment Outcome; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D014635:Valproic Acid