title: Histone Deacetylase Inhibition and IκB Kinase/Nuclear Factor-κB Blockade Ameliorate Microvascular Proinflammatory Responses Associated With Hemorrhagic Shock/Resuscitation in Mice.
abstract: OBJECTIVE
  To investigate the consequences of histone deacetylase inhibition by histone deacetylase inhibitor valproic acid and IκB kinase/nuclear factor-κB signaling blockade by IκB kinase inhibitor BAY11-7082 on (microvascular) endothelial cell behavior in vitro as well as in mice subjected to hemorrhagic shock/resuscitation in vivo.
  
  
  METHODS
  Prospective, randomized laboratory investigation using an established mouse model of hemorrhagic shock.
  
  
  METHODS
  Research laboratory at university teaching hospital.
  
  
  METHODS
  Endothelial cells and C57BL/6 male mice.
  
  
  METHODS
  Endothelial cells were incubated with tumor necrosis factor-α in the absence or presence of valproic acid or BAY11-7082 in vitro. Mice were subjected to hemorrhagic shock by blood withdrawn until the mean arterial pressure of 30 mm Hg and maintained at this pressure for 90 minutes. At 90 minutes, subgroups of mice were resuscitated with 4% human albumin in the absence or presence of vehicle, valproic acid (300 μg/g body weight) or BAY11-7082 (400 μg per mouse). Mice were killed 1 hour and 4 hours after resuscitation.
  
  
  RESULTS
  Valproic acid and BAY11-7082 selectively diminished tumor necrosis factor-α-induced endothelial proinflammatory activation in vitro. In vivo, both systemic and local inflammatory responses were significantly induced by hemorrhagic shock/resuscitation. The decreased histone acetylation in kidneys after hemorrhagic shock/resuscitation was restored by valproic acid treatment. In glomerular endothelial cells, the nuclear translocation of nuclear factor-κB, which was induced by hemorrhagic shock/resuscitation, was eliminated by BAY11-7082 treatment while enhanced in the presence of valproic acid. Both valproic acid and BAY11-7082 significantly attenuated the hemorrhagic shock/resuscitation-induced protein expression of endothelial cell adhesion molecules E-selectin and vascular cell adhesion molecule-1 in the microvasculature of kidneys and liver, although messenger RNA expression levels of these molecules analyzed in whole-organ lysates of kidneys, lungs, and liver were not extensively affected. The reduced protein expression of adhesion molecules was paralleled by diminishing the adhesion/transmigration of neutrophils in kidneys and liver after hemorrhagic shock/resuscitation.
  
  
  CONCLUSIONS
  Suppression of histone deacetylase activity and blockade of IκB kinase/nuclear factor-κB signaling during resuscitation ameliorate microvascular endothelial proinflammatory responses in organs in mice after hemorrhagic shock.
authors.affiliation: 1Medical Biology Section, Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 2Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 3Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Ranran
authors.initials: R
authors.lastname: Li
authors.forename: Adnan
authors.initials: A
authors.lastname: Aslan
authors.forename: Rui
authors.initials: R
authors.lastname: Yan
authors.forename: Rianne M
authors.initials: RM
authors.lastname: Jongman
authors.forename: Jill
authors.initials: J
authors.lastname: Moser
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Zwiers
authors.forename: Henk E
authors.initials: HE
authors.lastname: Moorlag
authors.forename: Jan G
authors.initials: JG
authors.lastname: Zijlstra
authors.forename: Grietje
authors.initials: G
authors.lastname: Molema
authors.forename: Matijs
authors.initials: M
authors.lastname: van Meurs
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D018836:Inflammation Mediators / Q000276:immunology; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009570:Nitriles / Q000494:pharmacology; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D056572:Histone Deacetylase Inhibitors; D018836:Inflammation Mediators; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D013450:Sulfones; D014635:Valproic Acid; D051550:I-kappa B Kinase; D006655:Histone Deacetylases