Experimental paperEffect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion☆
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).
References (33)
- et al.
Role of extracellular signal-regulated protein kinase (ERK) in 17beta-estradiol-mediated attenuation of lung injury after trauma-hemorrhage
Surgery
(2009) - et al.
Identification of a novel potential biomarker in a model of hemorrhagic shock and valproic acid treatment
J Surg Res
(2010) - et al.
Pharmacologic resuscitation: cell protective mechanisms of histone deacetylase inhibition in lethal hemorrhagic shock
J Surg Res
(2009) - et al.
Surviving blood loss without blood transfusion in a swine poly-trauma model
Surgery
(2009) - et al.
Cell protective mechanism of valproic acid in lethal hemorrhagic shock
Surgery
(2008) - et al.
a member of the interleukin-8 family, is a neutrophil-specific chemoattractant in vivo
Exp Mol Pathol
(1991) - et al.
Identification of a common receptor for three types of rat cytokine-induced neutrophil chemoattractants (CINCs)
Cytokine
(2000) - et al.
The novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin, prevents local and remote organ injury following intestinal ischemia/reperfusion in rats
J Surg Res
(2008) - et al.
Acetylation: a novel method for modulation of the immune response following trauma/hemorrhage and inflammatory second hit in animals and humans
Surgery
(2008) - et al.
Valproic acid-mediated neuroprotection in intracerebral hemorrhage via histone deacetylase inhibition and transcriptional activation
Neurobiol Dis
(2007)
Impact of resuscitation strategies on the acetylation status of cardiac histones in a swine model of hemorrhage
Resuscitation
Chronic treatment with mood stabilizers lithium and valproate prevents excitotoxicity by inhibiting oxidative stress in rat cerebral cortical cells
Biol Psychiatry
Role of glutathione in neuroprotective effects of mood stabilizing drugs lithium and valproate
Neuroscience
Cytoprotection by lithium and valproate varies between cell types and cellular stresses
Eur J Pharmacol
Reperfusion injury after intestinal ischemia
Crit Care Med
Post-injury multiple organ failure: the role of the gut
Shock
Cited by (69)
Natural therapeutics and nutraceuticals for lung diseases: Traditional significance, phytochemistry, and pharmacology
2022, Biomedicine and PharmacotherapyHidden pharmacological activities of valproic acid: A new insight
2021, Biomedicine and PharmacotherapyIntestinal ischemic reperfusion injury: Recommended rats model and comprehensive review for protective strategies
2021, Biomedicine and PharmacotherapyCitation Excerpt :Other strains of rats were rarely used in researches. 51 of 57 studies used male rats [1,3,5,12,15,17–29,31–37,39–46,48–52,54–62,64–67]. 4 researches applied female rats [38,47,53,63], and other studies did not state the gender [16,30].
Nervilifordin F alleviates intestinal ischemia/reperfusion-induced acute lung injury via inhibiting inflammasome and mTOR pathway
2020, International ImmunopharmacologyMiR-23a-5p exacerbates intestinal ischemia–reperfusion injury by promoting oxidative stress via targeting PPAR alpha
2020, Biochemical Pharmacology
- ☆
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.