title: Acetylation: a novel method for modulation of the immune response following trauma/hemorrhage and inflammatory second hit in animals and humans.
abstract: BACKGROUND
  Hemorrhage induces an imbalance in histone acetyl transferase/histone deacetylase (HAT/HDAC) ratio. Correction of this imbalance with histone deacetylase inhibitors (HDACI) improves survival. We aimed to identify whether this was due to modulation of the post-shock immune response.
  
  
  METHODS
  We established a "two-hit" model in which rats (n=11; 5-6/group) and humans (n=10; 5/group) sustained trauma/hemorrhage, followed by exposure of splenic leukocytes to lipopolysaccharide (LPS, 10 ng/mL) for 8 or 24 hours. The leukocytes were treated with: No treatment, SAHA (suberoylanilide hydroxamic acid, HDACI, 400 nM), or Garcinol (HAT inhibitor, 20 microM).
  
  
  RESULTS
  Hemorrhage in the animals produced severe shock and a pro-inflammatory state. SAHA reduced TNFa secretion in the hemorrhaged leukocytes after LPS "second-hit" (34.0%, P = .003), whereas it increased transcript levels of TNFa and IL-1b (2.1+/-0.3 and 5.1+/- 2.2 fold respectively, P < .05). Leukocytes from trauma patients displayed 2 distinct responses to SAHA after LPS "second-hit," with markedly increased or decreased cytokine levels.
  
  
  CONCLUSIONS
  SAHA normalizes TNFa levels following hemorrhage and LPS "second hit" in the rats, whereas trauma patients respond to SAHA in 2 distinct patterns, with either marked attenuation or exaggeration of inflammatory cytokines. Cytokine levels were independent of gene expression, implicating acetylation of non-nuclear proteins as the dominant regulatory mechanism.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sailhamer
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Smith
authors.forename: Fahad
authors.initials: F
authors.lastname: Shuja
authors.forename: Christian
authors.initials: C
authors.lastname: Shults
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Chad
authors.initials: C
authors.lastname: Soupir
authors.forename: Marc
authors.initials: M
authors.lastname: deMoya
authors.forename: George
authors.initials: G
authors.lastname: Velmahos
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000007:Abdominal Injuries / Q000378:metabolism*; D000107:Acetylation; D000328:Adult; D000818:Animals; D018929:Cell Culture Techniques; D005260:Female; D006470:Hemorrhage / Q000378:metabolism / Q000503:physiopathology; D051548:Histone Acetyltransferases / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007249:Inflammation; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D012771:Shock, Hemorrhagic / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D013154:Spleen / Q000378:metabolism; D013156:Splenectomy; D018746:Systemic Inflammatory Response Syndrome / Q000209:etiology / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases