Creating a Prosurvival Phenotype Through a Histone Deacetylase Inhibitor in a Lethal Two-Hit Model

Zhengcai Liu, Yongqing Li, Wei Chong, Danielle K. Deperalta, Xiuzhen Duan, Baoling Liu, Ihab Halaweish, Peter Zhou, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

ABSTRACT: Objectives: Hemorrhagic shock (HS) can initiate an exaggerated systemic inflammatory response and multiple organ failure, especially if followed by a subsequent inflammatory insult ("second hit"). We have recently shown that histone deacetylase inhibitors can improve survival in rodent models of HS or septic shock, individually. In the present study, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, could prolong survival in a rodent "two-hit" model: HS followed by septic shock from cecal ligation and puncture (CLP). Methods: Male Sprague-Dawley rats (250-300 g) were subjected to sublethal HS (40% blood loss) and then randomly divided into two groups (n = 7/group): VPA and control. The VPA group was treated intraperitoneally with VPA (300 mg/kg in normal saline [NS], volume = 750 μL/kg). The control group was injected with 750 μL/kg NS. After 24 h, all rats received CLP followed immediately by injection of the same dose of VPA (VPA group) or NS (vehicle group). Survival was monitored for 10 days. In a parallel study, serum and peritoneal irrigation fluid from VPA- or vehicle-treated rats were collected 3, 6, and 24 h after CLP, and enzyme-linked immunosorbent assay was performed to analyze myeloperoxidase activity and determine tumor necrosis factor α and interleukin 6 concentrations. Hematoxylin-eosin staining of lungs at 24-h time point was performed to investigate the grade of acute lung injury. Results: Rats treated with VPA (300 mg/kg) showed significantly higher survival rates (85.7%) compared with the control (14.3%). Moreover, VPA significantly suppressed myeloperoxidase activity (marker of neutrophil-mediated oxidative damage) and inhibited levels of proinflammatory cytokine tumor necrosis factor α and interleukin 6 in the serum and peritoneal cavity. Meanwhile, the severity of acute lung injury was significantly reduced in VPA-treated animals. Conclusions: We have demonstrated that VPA treatment improves survival and attenuates inflammation in a rodent two-hit model.

Original languageEnglish (US)
Pages (from-to)104-108
Number of pages5
JournalShock
Volume41
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • acetylation
  • acute lung injury
  • cytokine
  • Hemorrhage
  • resuscitation
  • sepsis
  • shock
  • survival
  • valproic acid

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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