title: Surviving lethal septic shock without fluid resuscitation in a rodent model.
abstract: BACKGROUND
  We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model.
  
  
  METHODS
  C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay.
  
  
  RESULTS
  All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations.
  
  
  CONCLUSIONS
  We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Fukudome
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Kochanek
authors.forename: Robert A
authors.initials: RA
authors.lastname: Finkelstein
authors.forename: Wei
authors.initials: W
authors.lastname: Chong
authors.forename: Guang
authors.initials: G
authors.lastname: Jin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lu
authors.forename: Marc A
authors.initials: MA
authors.lastname: deMoya
authors.forename: George C
authors.initials: GC
authors.lastname: Velmahos
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005440:Fluid Therapy; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D012151:Resuscitation; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D000077337:Vorinostat
chemical_list: D017931:DNA Primers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat