TY - JOUR
T1 - Novel pharmacologic treatment attenuates septic shock and improves long-term survival
AU - Zhao, Ting
AU - Li, Yongqing
AU - Liu, Baoling
AU - Liu, Zhengcai
AU - Chong, Wei
AU - Duan, Xiuzhen
AU - Deperalta, Danielle K.
AU - Velmahos, George C.
AU - Alam, Hasan B.
N1 - Funding Information:
Supported by a grant from NIH RO1 GM084127 to HBA.
Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/8
Y1 - 2013/8
N2 - 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 marrow-derived 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.
AB - 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 marrow-derived 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.
UR - http://www.scopus.com/inward/record.url?scp=84880859481&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84880859481&partnerID=8YFLogxK
U2 - 10.1016/j.surg.2013.04.003
DO - 10.1016/j.surg.2013.04.003
M3 - Article
C2 - 23889949
AN - SCOPUS:84880859481
SN - 0039-6060
VL - 154
SP - 206
EP - 213
JO - Surgery
JF - Surgery
IS - 2
ER -