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Surviving lethal septic shock without fluid resuscitation in a rodent model
Yongqing Li1, Baoling Liu, Eugene Y Fukudome
1Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
Surgery
|June 22, 2010
Summary
Administering suberoylanilide hydroxamic acid (SAHA) after lipopolysaccharide (LPS) exposure significantly improves rodent survival. SAHA treatment also reduces inflammatory markers, suggesting a potential therapeutic strategy for sepsis.
Area of Science:
- Pharmacology
- Immunology
- Molecular Biology
Background:
- Histone deacetylase inhibitors, like suberoylanilide hydroxamic acid (SAHA), have shown promise in improving survival when administered before lipopolysaccharide (LPS).
- Lipopolysaccharide (LPS) is a potent endotoxin that triggers a severe inflammatory response, leading to sepsis and shock.
Purpose of the Study:
- To investigate the efficacy of SAHA in improving survival and attenuating LPS-induced shock when administered *after* a lethal LPS insult.
- To explore the molecular mechanisms underlying SAHA's anti-inflammatory effects in a rodent model.
Main Methods:
- C57BL/6J mice were injected with LPS and treated with either vehicle (DMSO) or SAHA (50 mg/kg) 2 hours post-insult.
- Survival rates were monitored for 7 days.
- Gene expression of MyD88, TNF-alpha, and IL-6 in lung tissue was analyzed.
- RAW264.7 macrophages were used to assess SAHA's effect on LPS-induced inflammation via ELISA.
Main Results:
- SAHA treatment significantly improved 7-day survival in LPS-injected mice (80% vs. 0% in vehicle group).
- LPS challenge increased MyD88, TNF-alpha, and IL-6 expression and protein secretion.
- SAHA administration significantly attenuated these LPS-induced inflammatory responses.
Conclusions:
- Post-insult administration of SAHA (50 mg/kg) significantly enhances long-term survival following lethal LPS exposure.
- SAHA effectively attenuates the expression of pro-inflammatory mediators TNF-alpha and IL-6.
- The anti-inflammatory effects of SAHA may involve the downregulation of the MyD88-dependent pathway and associated pro-inflammatory genes.
