title: Ciglitazone ameliorates lung inflammation by modulating the inhibitor kappaB protein kinase/nuclear factor-kappaB pathway after hemorrhagic shock.
abstract: OBJECTIVE
  Peroxisome proliferator-activated receptor-gamma is a ligand-activated transcription factor. Ciglitazone, a peroxisome proliferator-activated receptor-gamma ligand, has been shown to provide beneficial effects in experimental models of sepsis and ischemia/reperfusion injury. We investigated the effects of ciglitazone on lung inflammation after severe hemorrhage.
  
  
  METHODS
  Prospective, laboratory study, rodent model of hemorrhagic shock.
  
  
  METHODS
  University hospital laboratory.
  
  
  METHODS
  Male rats.
  
  
  METHODS
  Hemorrhagic shock was induced by withdrawing blood to a mean arterial pressure of 50 mm Hg. At 3 hrs after hemorrhage, rats were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, animals received ciglitazone (10 mg/kg) or vehicle intraperitoneally. Heart rate and mean arterial pressure were measured throughout the experiment. Plasma and lung tissue were collected for analysis up to 3 hrs after resuscitation.
  
  
  RESULTS
  Ciglitazone treatment ameliorated mean arterial pressure, reduced lung injury, significantly blunted lung neutrophil infiltration, and lowered plasma interleukin-6, interleukin-10, and monocyte chemoattractant protein-1 levels. In a time course analysis, vehicle-treated rats had a significant increase in nuclear factor-kappaB DNA binding, which was preceded by increased inhibitor kappaB protein kinase activity and inhibitor kappaB alpha degradation in the lung. Treatment with ciglitazone significantly reduced inhibitor kappaB protein kinase activity and inhibitor kappaB alpha degradation and completely inhibited nuclear factor-kappaB DNA binding. This reduction of inhibitor kappaB protein kinase activity afforded by ciglitazone appeared to be a consequence of a physical interaction between peroxisome proliferator-activated receptor-gamma and increased inhibitor kappaB protein kinase.
  
  
  CONCLUSIONS
  Ciglitazone ameliorates the inflammatory response and may reduce lung injury after hemorrhagic shock. These protective effects appear to be mediated through inhibition of the inhibitor kappaB protein kinase/nuclear factor-kappaB pathway.
authors.affiliation: Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Ranjit S
authors.initials: RS
authors.lastname: Chima
authors.forename: Paul W
authors.initials: PW
authors.lastname: Hake
authors.forename: Giovanna
authors.initials: G
authors.lastname: Piraino
authors.forename: Prajakta
authors.initials: P
authors.lastname: Mangeshkar
authors.forename: Alvin
authors.initials: A
authors.lastname: Denenberg
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000097:blood*; D007263:Infusions, Parenteral; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009195:Peroxidase / Q000097:blood; D011014:Pneumonia / Q000473:pathology / Q000517:prevention & control*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012151:Resuscitation / Q000379:methods; D012680:Sensitivity and Specificity; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D018925:Chemokines; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; D009195:Peroxidase; C039671:ciglitazone