Protective effect of suberoylanilide hydroxamic acid against lps-induced septic shock in rodents

Yongqing Li, Baoling Liu, Hang Zhao, Elizabeth A. Sailhamer, Eugene Y. Fukudome, Xiaobo Zhang, Tareq Kheirbek, Robert A. Finkelstein, George C. Velmahos, Marc Demoya, Charles A. Hales, Hasan B. Alam

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-α in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-α and IL-1β genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.

Original languageEnglish (US)
Pages (from-to)517-523
Number of pages7
JournalShock
Volume32
Issue number5
DOIs
StatePublished - Nov 2009
Externally publishedYes

Keywords

  • Acetylation
  • Histone
  • LPS
  • Lung
  • Macrophage
  • Septic shock
  • Suberoylanilide hydroxamic acid
  • Survival

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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