title: Novel pharmacologic treatment attenuates septic shock and improves long-term survival.
abstract: 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.
  
  
  CONCLUSIONS
  SAHA treatment improves survival, decreases "cytokine storm," and prevents distant organ damage in a lethal septic model.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Zhengcai
authors.initials: Z
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Chong
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Duan
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Deperalta
authors.forename: George C
authors.initials: GC
authors.lastname: Velmahos
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D055371:Acute Lung Injury / Q000517:prevention & control; D000818:Animals; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D012772:Shock, Septic / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D051193:Toll-Like Receptors / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat
references.citation: N Engl J Med. 2012 May 31;366(22):2122-4
references.pmid: 22616829
references.citation: J Trauma Acute Care Surg. 2012 Feb;72(2):347-53; discussion 353-4
references.pmid: 22327976
references.citation: Surgery. 2010 Aug;148(2):246-54
references.pmid: 20561658
references.citation: J Biol Chem. 2009 Jun 19;284(25):17102-17109
references.pmid: 19386607
references.citation: Science. 2012 Jan 13;335(6065):229-32
references.pmid: 22246778
references.citation: Blood. 2007 Jan 1;109(1):31-9
references.pmid: 16960145
references.citation: J Exp Med. 2009 Aug 31;206(9):2027-35
references.pmid: 19703987
references.citation: CSH Protoc. 2008 Dec 01;2008:pdb.prot5080
references.pmid: 21356739
references.citation: Genes Dev. 2006 Feb 15;20(4):473-85
references.pmid: 16481475
references.citation: Oncogene. 2007 Aug 13;26(37):5541-52
references.pmid: 17694093
references.citation: J Surg Res. 2010 Sep;163(1):146-54
references.pmid: 20599223
references.citation: J Surg Res. 2012 Dec;178(2):851-9
references.pmid: 22868051
references.citation: Trends Immunol. 2011 Jul;32(7):335-43
references.pmid: 21570914
references.citation: Immunol Cell Biol. 2012 Jan;90(1):23-32
references.pmid: 22083527
references.citation: Eur J Immunol. 2004 Feb;34(2):558-64
references.pmid: 14768061
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15819-24
references.pmid: 19721002
references.citation: Shock. 2009 Nov;32(5):517-23
references.pmid: 19295477
references.citation: Nat Rev Immunol. 2008 Oct;8(10):776-87
references.pmid: 18802444
references.citation: N Engl J Med. 2012 May 31;366(22):2055-64
references.pmid: 22616830
references.citation: JAMA. 2011 Dec 21;306(23):2594-605
references.pmid: 22187279
references.citation: Semin Immunol. 2004 Feb;16(1):3-9
references.pmid: 14751757
references.citation: Surgery. 2012 Sep;152(3):455-64
references.pmid: 22938904
references.citation: Nat Protoc. 2009;4(1):31-6
references.pmid: 19131954
references.citation: Mol Med. 2012 May 09;18:455-65
references.pmid: 22252713
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2995-3000
references.pmid: 11867742