Am J Respir Crit Care Med. 2010 Aug 6. [Epub ahead of print]
Kapoor A, Shintani Y, Collino M, Osuchowski MF, Busch D, Patel NS, Sepodes B, Castiglia S, Fantozzi R, Bishop-Bailey D, Mota-Filipe H, Yaqoob MM, Suzuki K, Bahrami S, Desvergne B, Mitchell JA, Thiemermann C.
Centre for Translational Medicine & Therapeutics, William Harvey Research Institute, London, United Kingdom.
RATIONALE: PPAR-beta/delta is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-beta/delta in sepsis is unknown. OBJECTIVE: We investigated the role of PPAR-beta/delta in murine models of lipopolysaccharide (LPS)-induced organ injury/dysfunction and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. METHODS: Wild-type (WT) and PPAR-beta/delta knockout (KO) mice, and C57BL/6 mice were subjected to LPS for 16 h. C57BL/6 mice received the PPAR-beta/delta agonist GW0742 (0.03 mg/kg intravenously, 1 h after LPS) or GW0742 plus the PPAR-beta/delta 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-beta/delta KO mice, endotoxemia exacerbated organ injury/dysfunction (cardiac, renal, hepatic) and inflammation (lung) when compared to WT-mice. In C57BL/6 mice subjected to endotoxemia, GW0742 significantly (i) attenuated organ (cardiac, renal) dysfunction and inflammation (lung), (ii) increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3beta, (iii) attenuated the decrease in extracellular signal-regulated kinase (ERK)1/2 and signal transducer and activator of transcription (STAT)-3 phosphorylation, and (iv) attenuated the activation of nuclear factor (NF)-kappaB 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-beta/delta antagonist GSK0660. CONCLUSIONS: PPAR-beta/delta protects against multiple organ injury/dysfunction and inflammation caused by endotoxic shock and improves survival in polymicrobial sepsis by a mechanism that may involve activation of the Akt and inhibition of GSK-3beta and NF-kappaB.