Pioglitazone reduces inflammation through inhibition of nuclear factor kappa-B in polymicrobial sepsis

• Published in: Innate immunity (London, England) England), 2013-09, Vol.20 (5), p.519-528
• Main Authors: Kaplan, Jennifer, Nowell, Marchele, Chima, Ranjit, Zingarelli, Basilia
• Format: Article
• Language: English
• ISSN: 1753-4259; 1753-4267
• DOI: 10.1177/1753425913501565

The insulin sensitizing thiazolidinedione drugs, rosiglitazone and pioglitazone are specific peroxisome proliferator-activated receptor-gamma (PPARγ) 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 22g double puncture technique. Mice received intraperitoneal injection of vehicle (DMSO:PBS) or pioglitazone (20mg/kg) at 1h and 6h after CLP and were sacrificed at various timepoints. 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 glucose and adiponectin levels and decreased pro-inflammatory cytokines. Lung IκBα protein expression increased and corresponded with a decrease in nuclear factor kappa-B (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.