Amar Kapoor1, Yasunori Shintani1, Massimo Collino2, Marcin F. Osuchowski3, Daniel Busch3, Nimesh S. A. Patel1, Bruno Sepodes4, Sara Castiglia2, Roberto Fantozzi2, David Bishop-Bailey1, Helder Mota-Filipe4, Muhammad M. Yaqoob1, Ken Suzuki1, Soheyl Bahrami3, Béatrice Desvergne5, Jane A. Mitchell6 and Christoph Thiemermann1. Published ahead of print on August 6, 2010, doi:10.1164/rccm.201002-0240OC. American Journal of Respiratory and Critical Care Medicine Vol 182. pp. 1506-1515, (2010)
Rationale: Peroxisome proliferator–activated receptor (PPAR)-β/ is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-β/ in sepsis is unknown.

Objectives: We investigated the role of PPAR-β/ 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/ knockout (KO) mice and C57BL/6 mice were subjected to LPS for 16 hours. C57BL/6 mice received the PPAR-β/ agonist GW0742 (0.03 mg/kg intravenously, 1 h after LPS) or GW0742 plus the PPAR-β/ 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/ 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)-B 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/ antagonist GSK0660.

Conclusions: PPAR-β/ 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-B.

Weblink here