title: Protective effect of suberoylanilide hydroxamic acid against lipopolysaccharide-induced liver damage in rodents.
abstract: BACKGROUND
  Lipopolysaccharide (LPS) has a deleterious effect on several organs, including the liver, and eventually leads to endotoxic shock and death. LPS-induced hepatotoxicity is characterized by disturbed intracellular redox balance and excessive reactive oxygen species (ROS) accumulation, leading to liver injury. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a murine model of LPS-induced shock, but the protective effect of SAHA against liver damage remains unknown. The goal of this study was to investigate the mechanism underlying SAHA action in murine livers.
  
  
  METHODS
  Male C57BL/6J mice (6-8 wk), weighing 20-25 g, were randomly divided into three groups: (A) a sham group was given isotonic sodium chloride solution (10 μL/g body weight, intraperitoneal, i.p.) with dimethyl sulfoxide (DMSO; 1 μL/g body weight, i.p.); (B) an LPS group was challenged with LPS (20 mg/kg, i.p.) dissolved in isotonic sodium chloride solution with DMSO; (C) and an LPS plus SAHA group was treated with SAHA (50 mg/kg, i.p.) dissolved in DMSO immediately after injection of LPS (20 mg/kg, i.p.). Mice were anesthetized, and their livers were harvested 6 or 24 h after injection to analyze whether SAHA affected production of ROS and activation of apoptotic proteins in the liver cells of challenged mice.
  
  
  RESULTS
  SAHA counteracted LPS-induced production of ROS (thiobarbituric acid reactive substances and nitrite) and reversed an LPS-induced decrease in antioxidant enzyme, glutathione. SAHA also attenuated LPS-induced hepatic apoptosis. Moreover, SAHA inhibited activation of the redox-sensitive kinase, apoptosis signal-regulating kinase-1, and the mitogen-activated protein kinases, p38 and Jun N-terminal kinase.
  
  
  CONCLUSIONS
  Our data indicate, for the first time, that SAHA is capable of alleviating LPS-induced hepatotoxicity and suggest that a blockade of the upstream events required for apoptosis signal-regulating kinase-1 action may serve as a new therapeutic option in the treatment of LPS-induced inflammatory conditions.
authors.affiliation: School of Arts and Sciences, Tufts University, Medford, Massachusetts.
authors.forename: Yili
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Harvard University, Cambridge, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.affiliation: Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan.
authors.forename: Ted
authors.initials: T
authors.lastname: Bambakidis
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ralph
authors.initials: R
authors.lastname: Mazitschek
authors.affiliation: Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: alamh@med.umich.edu.
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
authors.affiliation: Trauma Translational & Clinical Research, Section of General Surgery, University of Michigan Hospital, Ann Arbor, Michigan. Electronic address: yqli@med.umich.edu.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011897:Random Allocation; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D000077337:Vorinostat; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053453:Caspase 9
keywords: Apoptosis; Histone deacetylase inhibitor; Inflammation; LPS; Liver