Background
We have previously demonstrated that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lipopolysaccharide (LPS)-induced lethal endotoxemia model. The goal of this study was to investigate the impact of SAHA on survival in a more clinically relevant cecal ligation and puncture (CLP)-induced septic shock model, and to elucidate changes in cytokine responses and organ injury.
Methods
C57BL/6J mice were subjected to CLP, and 1 hour later given either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only, intra-peritoneal. Survival was monitored for 10 days. In a second study, livers were harvested for evaluation of acute liver injury, and peritoneal fluid and blood samples were collected for cytokine assays. In addition, RAW264.7 and bone marrow-derived macrophages (BMMs) were utilized to assess effects of SAHA on cytokine responses.
Results
SAHA treated animals displayed a significant improvement in survival. In addition, SAHA also significantly attenuated cytokine levels in blood and peritoneal fluid compared to vehicle animals, as well as in culture supernatant of macrophages stimulated with bacterial components (LPS or Pam3CSK4). Moreover, SAHA treated animals showed a significant decrease in acute liver injury.
Conclusions
SAHA treatment improves survival, reduces “cytokine storm”, and prevents distant organ damage in a lethal septic model.