RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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: Jianmin Chen; Julius E Kieswich; Fausto Chiazza; Amie J Moyes; Thomas Gobbetti; Gareth S D Purvis; Daniela C F Salvatori; Nimesh S A Patel; Mauro Perretti; Adrian J Hobbs; Massimo Collino; Muhammad M Yaqoob; Christoph Thiemermann Journal: J Am Soc Nephrol Date: 2016-05-06 Impact factor: 10.121
Authors: Raymond J Langley; Ephraim L Tsalik; Jennifer C van Velkinburgh; Seth W Glickman; Brandon J Rice; Chunping Wang; Bo Chen; Lawrence Carin; Arturo Suarez; Robert P Mohney; Debra H Freeman; Mu Wang; Jinsam You; Jacob Wulff; J Will Thompson; M Arthur Moseley; Stephanie Reisinger; Brian T Edmonds; Brian Grinnell; David R Nelson; Darrell L Dinwiddie; Neil A Miller; Carol J Saunders; Sarah S Soden; Angela J Rogers; Lee Gazourian; Laura E Fredenburgh; Anthony F Massaro; Rebecca M Baron; Augustine M K Choi; G Ralph Corey; Geoffrey S Ginsburg; Charles B Cairns; Ronny M Otero; Vance G Fowler; Emanuel P Rivers; Christopher W Woods; Stephen F Kingsmore Journal: Sci Transl Med Date: 2013-07-24 Impact factor: 17.956
Authors: Raymond J Langley; Jennifer L Tipper; Shannon Bruse; Rebecca M Baron; Ephraim L Tsalik; James Huntley; Angela J Rogers; Richard J Jaramillo; Denise O'Donnell; William M Mega; Mignon Keaton; Elizabeth Kensicki; Lee Gazourian; Laura E Fredenburgh; Anthony F Massaro; Ronny M Otero; Vance G Fowler; Emanuel P Rivers; Chris W Woods; Stephen F Kingsmore; Mohan L Sopori; Mark A Perrella; Augustine M K Choi; Kevin S Harrod Journal: Am J Respir Crit Care Med Date: 2014-08-15 Impact factor: 21.405
Authors: Baktybek Kojonazarov; Himal Luitel; Akylbek Sydykov; Bhola K Dahal; Mark J Paul-Clark; Sara Bonvini; Anna Reed; Ralph T Schermuly; Jane A Mitchell Journal: Pulm Circ Date: 2013-12 Impact factor: 3.017