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Pretreatment with troglitazone decreases lethality during endotoxemia in mice

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA, Department of Radiologic Technology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Bo Novosad

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA, Department of Radiologic Technology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Adam Hoffhines

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA

Jenny Gipson

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA

Jared Johnson

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA

Jeffrey Peters

Department of Veterinary Science, Pennsylvania State University, University Park, Pennsylvania, USA

Frank Gonzalez

Laboratory of Metabolism, NCI, National Institutes of Health, Bethesda, Maryland, USA

Jeffrey Gimble

Tissue Engineering Program, Artecell Inc., Durham, North Carolina, USA

Molly Hill

Department of Natural Sciences, Oklahoma Christian University, Oklahoma City, Oklahoma, USA, Molly.Hill{at}oc.edu, Department of Radiologic Technology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Troglitazone is an oral antidiabetic drug that is a ligand for peroxisome proliferator activated receptor (PPAR). Based on other studies that have implicated an immunosuppressive role for PPAR during inflammatory responses, we hypothesized that troglitazone treatment would improve survival in a murine model of endotoxemia and that the protective effect would be mediated by decreased expression of inflammatory mediators. C57Bl/6N x Sv/129 (wild-type [WT]) or PPAR null mice treated for 2 weeks with dietary troglitazone (0.1%) had significantly fewer deaths and a higher LD ₅₀ value compared to control-fed mice when challenged with lipopolysaccharide (LPS). PPAR null mice were more sensitive to the lethal effects of LPS as evidenced by a 2-fold lower LD ₅₀ (6.6 mg/kg) compared to WT mice (14.6 mg/kg). Troglitazone treatment had no significant effect on LPS-induced plasma TNF, glucose, or nitric oxide levels in WT or PPAR null mice at any of the time points examined. However, troglitazone treatment significantly reduced LPS-induced plasma IL-6 levels in both WT and PPAR null mice. The results of these studies suggest that troglitazone treatment protects mice against a lethal challenge of LPS, but whether or not this effect is mediated through decreased expression of inflammatory mediators remains unclear.

Journal of Endotoxin Research, Vol. 8, No. 4, 307-314 (2002)
DOI: 10.1177/09680519020080040701


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