Pharmacologic resuscitation promotes survival and attenuates hemorrhage-induced activation of extracellular signal-regulated kinase 1/2

Eugene Y. Fukudome, Ashley R. Kochanek, Yongqing Li, Eleanor J. Smith, Baoling Liu, Tareq Kheirbek, Jennifer Lu, Kyuseok Kim, Kristopher Hamwi, George C. Velmahos, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Background: Hemorrhage is the leading cause of preventable trauma-related deaths, and histone deacetylase inhibitors (HDACI) such as valproic acid (VPA) can improve survival following lethal hemorrhage. HDACI acetylate proteins, and acetylation regulates many cellular functions. Here we have investigated the effects of VPA treatment on extracellular signal-regulated kinase 1/2 (ERK) activation, as ERK is well known to modulate cell death, gene expression, and inflammation. Materials and Methods: Anesthetized Wistar-Kyoto rats were subjected to lethal (60%) blood loss, and then randomized (n = 5-6/group) to (1) VPA 300 mg/kg or (2) vehicle control. Survival was monitored for 24 h. A separate group of rats were subjected to sublethal (40%) hemorrhage and were treated with VPA or vehicle. Rats were sacrificed at 1, 4, and 20 h, and lung tissue was assessed for the degree of acetylation of histone 3, and activation (phosphorylation) of ERK. Sham animals served as normal controls. Results: Sixty percent hemorrhage resulted in severe shock. Only 17% of the vehicle-treated animals survived (most died within 1 h), whereas 80% of the VPA-treated animals survived (P < 0.05). Hemorrhage resulted in a significant increase in phosphorylated ERK (activated form) compared with sham at the 1 and 4 h time points, but not at the 20 h time point. VPA treatment significantly attenuated these changes, while increasing histone protein acetylation. Conclusions: VPA treatment significantly improves survival following lethal hemorrhagic shock. Hemorrhage induces ERK activation, which is significantly attenuated by VPA treatment. This may represent one mechanism through which VPA promotes survival in otherwise lethal hemorrhagic shock.

Original languageEnglish (US)
Pages (from-to)118-126
Number of pages9
JournalJournal of Surgical Research
Volume163
Issue number1
DOIs
StatePublished - Sep 2010
Externally publishedYes

Keywords

  • acetylation
  • ERK
  • hemorrhage
  • lung
  • resuscitation
  • shock
  • survival
  • valproic acid

ASJC Scopus subject areas

  • Surgery

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