title: Protective role of peroxisome proliferator-activated receptor-β/δ in septic shock.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor (PPAR)-β/δ is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-β/δ in sepsis is unknown.
  
  
  OBJECTIVE
  We investigated the role of PPAR-β/δ in murine models of LPS-induced organ injury and dysfunction and cecal ligation and puncture (CLP)-induced polymicrobial sepsis.
  
  
  METHODS
  Wild-type (WT) and PPAR-β/δ knockout (KO) mice and C57BL/6 mice were subjected to LPS for 16 hours. C57BL/6 mice received the PPAR-β/δ agonist GW0742 (0.03 mg/kg intravenously, 1 h after LPS) or GW0742 plus the PPAR-β/δ antagonist GSK0660 (0.1 mg/kg intravenously, 30 min before LPS). CD-1 mice subjected to CLP received GW0742 or GW0742 plus GSK0660.
  
  
  RESULTS
  In PPAR-β/δ KO mice, endotoxemia exacerbated organ injury and dysfunction (cardiac, renal, and hepatic) and inflammation (lung) compared with WT mice. In C57BL/6 mice subjected to endotoxemia, GW0742 significantly (1) attenuated organ (cardiac and renal) dysfunction and inflammation (lung); (2) increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3β; (3) attenuated the increase in extracellular signal-regulated kinase (ERK)1/2 and signal transducer and activator of transcription (STAT)-3 phosphorylation; and (4) attenuated the activation of nuclear factor (NF)-κB and the expression of inducible nitric oxide synthase (iNOS). In CD-1 mice subjected to CLP, GW0742 improved 10-day survival. All the observed beneficial effects of GW0742 were attenuated by the PPAR-β/δ antagonist GSK0660.
  
  
  CONCLUSIONS
  PPAR-β/δ protects against multiple organ injury and dysfunction, and inflammation caused by endotoxic shock and improves survival in polymicrobial sepsis by a mechanism that may involve activation of Akt and inhibition of GSK-3β and NF-κB.
authors.affiliation: Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, London, United Kingdom.
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Marcin F
authors.initials: MF
authors.lastname: Osuchowski
authors.forename: Daniel
authors.initials: D
authors.lastname: Busch
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Bruno
authors.initials: B
authors.lastname: Sepodes
authors.forename: Sara
authors.initials: S
authors.lastname: Castiglia
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
authors.forename: Helder
authors.initials: H
authors.lastname: Mota-Filipe
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Yaqoob
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.forename: Soheyl
authors.initials: S
authors.lastname: Bahrami
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism / Q000517:prevention & control*; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D047494:PPAR delta; D048068:PPAR-beta; D051057:Proto-Oncogene Proteins c-akt; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; C529769:GSK0660; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C000605507:Gsk3b protein, mouse