Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion

Objectives: 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 (1 h) and reperfusion (3 h). They were randomized into 2 groups (n=7 per group) 30. min after ischemia: Vehicle (Veh) and VPA (300. mg/kg, IV). Primary end-point for this study was survival over 4. h from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3. h (1. h ischemia. +. 2. h 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). Conclusion: 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.