title: Pioglitazone reduces inflammation through inhibition of NF-κB in polymicrobial sepsis.
abstract: The insulin sensitizing thiazolidinedione drugs, rosiglitazone and pioglitazone are specific peroxisome proliferator-activated receptor-gamma agonists and reduce pro-inflammatory responses in patients with type 2 diabetes and coronary artery disease, and may be beneficial in sepsis. Sepsis was induced in 8-10-wk-old C57BL/6 mice by cecal ligation and puncture (CLP) with a 22 -g double puncture technique. Mice received an i.p. injection of vehicle (DMSO:PBS) or pioglitazone (20 mg/kg) at 1 h and 6 h after CLP, and were sacrificed at various time points. In sepsis, vehicle-treated mice had hypoglycemia, increased lung injury and increased lung neutrophil infiltration. Pro-inflammatory plasma cytokines were increased, but the plasma adipokine, adiponectin, was decreased in vehicle-treated septic mice. This corresponded with inhibitor κB (IκBα) protein degradation and an increase in NF-κB activity in lung. Pioglitazone treatment improved plasma Glc and adiponectin levels, and decreased pro-inflammatory cytokines. Lung IκBα protein expression increased and corresponded with a decrease in NF-κB activity in the lung from pioglitazone-treated mice. Pioglitazone reduces the inflammatory response in polymicrobial sepsis in part through inhibition of NF-κB and may be a novel therapy in sepsis.
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Jennifer.Kaplan@cchmc.org.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kaplan
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Marchele
authors.initials: M
authors.lastname: Nowell
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Chima
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: Basilia
authors.initials: B
authors.lastname: Zingarelli
mesh_terms: D054392:Adipokines / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D007003:Hypoglycemia / Q000150:complications / Q000473:pathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000032:analysis*; D047495:PPAR gamma / Q000097:blood; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000097:blood; D018805:Sepsis / Q000188:drug therapy* / Q000473:pathology; D045162:Thiazolidinediones / Q000627:therapeutic use*
chemical_list: D054392:Adipokines; D016207:Cytokines; D007004:Hypoglycemic Agents; D020672:I-kappa B Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D045162:Thiazolidinediones; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2; D000077205:Pioglitazone
keywords: NF-κB; Sepsis; inflammation; pioglitazone
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