Protective Role of Peroxisome Proliferator-activated Receptor-β/δ in Septic Shock

摘要

Rationale. Peroxisome proliferator-activated receptor (PPAR)-p/5 is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-p/5 in sepsis is unknown. Objectives: We investigated the role of PPAR-p/5 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-p/5 knockout (KO) mice and C57BL/6 mice were subjected to LPS for 16 hours. C57BL/6 mice received the PPAR-P/8 agonist GW0742 (0.03 mg/kg intrave-nously, 1 h after LPS) or GW0742 plus the PPAR-p/5 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-p/8 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 (7) attenuated organ (cardiac and renal) dysfunction and inflam-mation (lung); (2) increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3P; (3) attenuated the increase in extracellular signal-regulated kinase (ERK)1/2 and signal trans-ducer and activator of transcription (STAT)-3 phosphorylation; and (4) attenuated the activation of nuclear factor (NF)-kB 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-p/5 antagonist GSK0660. Conclusions: PPAR-P/8 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-3p and NF-kB.