Elsevier

Resuscitation

Volume 83, Issue 2, February 2012, Pages 243-248
Resuscitation

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

https://doi.org/10.1016/j.resuscitation.2011.07.029Get rights and content

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 (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.

Introduction

Intestinal ischemia and reperfusion (I/R) injury occurs in the setting of various clinical situations, such as necrotizing enterocolitis, midgut volvulus, intussusception, mesenteric ischemia, hemorrhagic and septic shock.1 Intestinal I/R injury has been shown not only to cause local damage to the bowel but also to release numerous mediators in the circulation that can cause multiple organ failure including acute lung injury (ALI).2 Among these mediators, reactive oxygen species (ROS) play a critical role in the development of ALI. Administration of anti-oxidants has been shown to decrease this injury in various models including hemorrhagic shock, intestine I/R, and sepsis.3 Similarly, activated neutrophils in the circulation have been identified as important inducers of distant organ injury, especially ALI.4 Cytokine-induced neutrophil chemoattractant (CINC) is a potent neutrophil chemotactic factor. An increase in CINC expression promotes neutrophils aggregation in the lung leading to severe inflammatory reaction and exuberant free radical generation, which eventually culminates in the development of ALI.5, 6

Numerous strategies have been tried to attenuate neutrophil mediated inflammatory damage to the lung, without much success.7, 8, 9 Valproic acid (VPA), used as anti-epileptic agent for decades, has recently been identified to have cell protective, anti-inflammatory, and anti-apoptotic properties after being tested in various ischemia reperfusion models.10, 11, 12, 13, 14 However, these properties of VPA have not been evaluated in the setting of intestinal I/R injury. We hypothesized that VPA administration may mitigate the deleterious effects of intestinal I/R injury and improve survival by decreasing the post-inflammatory ALI.

In the present study, we investigated two possible effects of VPA in a rat model of intestinal I/R injury: (1) whether treatment with VPA improves short term survival; and (2) whether it can attenuate immune-mediated acute lung injury, as measured by alteration in pulmonary histology and tissue levels of CINC, MPO and 8-isoprostane, and circulating interleukin-6 levels.

Section snippets

Materials and methods

All the research was conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals. The study adhered to the principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, and was approved by the Institutional Animal Care and Use Committee.

Survival study

As shown in Fig. 1, following intestinal I/R injury, all rats in the Veh control group died in less than 4 h (213 ± 48 min). However, VPA treated animals displayed significantly longer survival time (277 ± 72 min). The 4-h survival rate (1 h ischemia + 3 h reperfusion) in the VPA group was significantly higher, compared to the control.

Acute lung injury study

As shown in Table 1 and Fig. 2, the intestinal I/R increased the lung histological score (5.3 ± 0.6; Fig. 2A and B). This injury was significantly attenuated by VPA treatment

Discussion

In this study, we have demonstrated that VPA treatment improves survival in a rat model of intestinal I/R. We have also identified some of the underlying mechanisms for this protective effect: amelioration of ALI, inhibition of CINC, MPO and 8-isoprostane in lung, and reduction of IL-6 in serum. To the best of our knowledge, this is the first study that evaluates the effect of VPA on survival and distant organ damage (acute lung injury) after intestinal I/R.

It has been proposed that intestinal

Conflict of interest

None of the authors have any conflicts of interest to declare.

Acknowledgement

Supported by NIH RO1 GM084127 (to HBA). Data presented at the 6th Annual Academic Surgical Congress, Huntington Beach, CA (February, 2011).

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    A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.07.029.

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