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Comparative Study
. 2012 Feb;83(2):243-8.
doi: 10.1016/j.resuscitation.2011.07.029. Epub 2011 Aug 6.

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

Kyuseok Kim  1 , Yongqing Li, Guang Jin, Wei Chong, Baoling Liu, Jennifer Lu, Kyoungbun Lee, Marc Demoya, George C Velmahos, Hasan B Alam
Affiliations
Comparative Study

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

Kyuseok Kim et al. Resuscitation. 2012 Feb.

Abstract

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 (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).

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.

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Conflict of interest statement

Conflict of Interest Statement

None of the authors have any conflicts of interest to declare

Figures

Figure 1
Figure 1. Effect of VPA on 4 hour survival of animals after intestinal ischemia
Male Sprague-Dawley rats were subjected to intestinal ischemia and reperfusion. They were randomized into 2 groups (n = 7/group) 30 min after ischemia: Vehicle (Veh) control and VPA. Survival rates were recorded for ~4 hours. Kaplan-Meier curves were used for the comparison of survival rates between the Veh control and VPA groups. The symbol * indicates that a value significantly (p<0.05) differs from the control group.
Figure 2
Figure 2. VPA treatment attenuated acute lung injury
Acute lung injury was scored as described in Materials and Methods and expressed as mean values ± SD (n = 9 per group). The symbol * indicates that a value significantly differs from control group (p < 0.05). Representative histological sections of a lung from animal groups of the vehicle control and VPA treatment. VPA group had less alveolar congestion, neutrophil infiltration, and alveolar wall thickness. Hematoxylin & eosin staining; original magnification, X40.
Figure 3
Figure 3. CINC and Myeloperoxidase (MPO) activity in lung (n=9 animals per group)
Levels of CINC and myeloperoxidase (MPO) were analyzed from lung tissues of rats treated with or without VPA after intestinal ischemia. Values represent the means ± SD (n=9). The symbol * indicates that a value significantly (p<0.05) differs from the control group.
Figure 4
Figure 4. VPA decreased levels of 8-isoprostane in lungs and IL-6 in serum
The levels of 8-isoprostane were analyzed in lung tissue of rats treated with or without VPA. Values represent means ± SD (n=9). The symbol * indicates that a value significantly (p<0.05) differs from the control group.
Figure 5
Figure 5. Effect of VPA on serum levels of IL-6, IL-10 and ratio of IL-6 to IL-10
The levels of serum IL-6 and IL-10 were measured in rats treated with or without VPA after ischemia. The ratio of IL-6 to IL-10 was calculated, and values represent the means ± SD (n=9). The symbol * indicates that a value significantly (p<0.05) differs from control group.
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References

    1. Schoenberg MH, Beger HG. Reperfusion injury after intestinal ischemia. Crit Care Med. 1993;21:1376–1386. - PubMed
    1. Hassoun HT, Kone BC, Mercer DW, Moody FG, Weisbrodt NW, Moore FA. Post-injury multiple organ failure: the role of the gut. Shock. 2001;15:1–10. - PubMed
    1. Fink MP. Reactive oxygen species as mediators of organ dysfunction caused by sepsis, acute respiratory distress syndrome, or hemorrhagic shock: potential benefits of resuscitation with Ringer's ethyl pyruvate solution. Curr Opin Clin Nutr Metab Care. 2002;5:167–174. - PubMed
    1. Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med. 2006;27:337–349. - PubMed
    1. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol. 2005;288:L3–L15. - PMC - PubMed

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