title: Inhibition of histone deacetylases protects septic mice from lung and splenic apoptosis.
abstract: BACKGROUND
  Epigenetic programming, dynamically regulated by histone acetylation, may play a key role in the pathophysiology of sepsis. We examined whether histone deacetylase (HDAC) can contribute to sepsis-associated inflammation and apoptosis.
  
  
  METHODS
  Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in BALB/c mice. An intraperitoneal injection of CG200745 (10 mg/kg), a novel broad-spectrum HDAC inhibitor, or valproic acid (500 mg/kg), a predominant inhibitor of class I HDACs, was given 3 h before surgery.
  
  
  RESULTS
  HDAC1, HDAC2, and HDAC3 protein levels were decreased in lungs after CLP. Furthermore, CLP-induced sepsis increased both histone H3 and H4 acetylation levels in lungs. When CG200745 was given, apoptosis induction was strongly suppressed in lungs and spleens of septic mice. This antiapoptotic effect of CG200745 was not accompanied by upregulation of antiapoptotic and downregulation of proapoptotic Bcl-2 family member proteins. Treatment with CG200745 failed to inhibit elevated levels of serum cytokines and prevent lung inflammation in septic mice. Valproic acid also showed antiapoptotic but not anti-inflammatory effects in septic mice.
  
  
  CONCLUSIONS
  These findings imply that HDAC inhibitors are a unique agent to prevent cell apoptosis in sepsis at their doses that do not improve inflammatory features, indicating that septic inflammation and apoptosis may not necessarily be essential for one another's existence. This study also represents the first report that CLP-induced sepsis downregulates HDACs. Nevertheless, the data with HDAC inhibitors suggest that imbalance in histone acetylation may play a contributory role in expression or repression of genes involved in septic cell apoptosis.
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan; Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takebe
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Oishi
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Aoki
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Takashina
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yokoo
authors.affiliation: Kanagawa Cancer Center Research Institute, Yokohama, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Department of Anesthesiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. Electronic address: yhattori@med.u-toyama.ac.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hattori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D057890:Epigenomics; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009281:Naphthalenes / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000201:enzymology / Q000473:pathology; D000099186:Histone Deacetylase 3
chemical_list: D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D009281:Naphthalenes; D000099186:Histone Deacetylase 3; C572619:N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-loxy)methyl)oct-2-enediamide; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse
keywords: Apoptosis; Epigenetics; Histone deacetylase inhibitor; Lung inflammation; Polymicrobial sepsis