Novel Pharmacological Treatment Attenuates Septic Shock and Improves Long-Term Survival

Background. We have demonstrated previously that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lipopolysaccharide-induced lethal model of endotoxemia. The goal of this study was to investigate the impact of SAHA on survival in a more clinically relevant model of cecal ligation and puncture (CLP)-induced septic shock and to elucidate changes in cytokine responses and organ injury. Methods. C57BL/6J mice were subjected to CLP, and 1 hour later were given intraperitoneally either SAHA dissolved in dimethyl sulfoxide or dimethyl sulfoxide only. 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 marrowderived macrophages were used to assess effects of SAHA on cytokine responses. Results. SAHA-treated animals displayed a substantial improvement in survival. In addition, SAHA also attenuated cytokine levels in blood and peritoneal fluid compared with vehicle animals, as well as in culture supernatant of macrophages stimulated with bacterial components (lipopolysaccharide or Pam3CSK4). Moreover, SAHA-treated animals showed a substantial decrease in acute liver injury. Conclusion. SAHA treatment improves survival, decreases ‘‘cytokine storm,’’ and prevents distant organ damage in a lethal septic model. (Surgery 2013;154:206-13.)