Surviving lethal septic shock without fluid resuscitation in a rodent model

Surgery. 2010 Aug;148(2):246-54. doi: 10.1016/j.surg.2010.05.003. Epub 2010 Jun 19.


Background: We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model.

Methods: C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay.

Results: All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations.

Conclusion: We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • DNA Primers / genetics
  • Disease Models, Animal
  • Fluid Therapy
  • Gene Expression / drug effects
  • Histone Deacetylase Inhibitors / administration & dosage
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / therapeutic use*
  • Inflammation Mediators / metabolism
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Lipopolysaccharides / toxicity
  • Lung / drug effects
  • Lung / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Myeloid Differentiation Factor 88 / genetics
  • Resuscitation
  • Shock, Septic / chemically induced
  • Shock, Septic / drug therapy*
  • Shock, Septic / genetics
  • Shock, Septic / metabolism
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • Vorinostat


  • DNA Primers
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Inflammation Mediators
  • Interleukin-6
  • Lipopolysaccharides
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Tumor Necrosis Factor-alpha
  • Vorinostat