GW0742, a selective PPAR-β/δ agonist, contributes to the resolution of inflammation after gut ischemia/reperfusion injury

Rosanna Di Paola, Emanuela Esposito, Emanuela Mazzon, Irene Paterniti, Maria Galuppo, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

Abstract

PPARs belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: α, β/δ, and γ, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes, such as regulation of glucose and lipid redistribution. They also have antiatherogenic, anti-inflammatory, as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with I/R. This study investigated the effects of GW0742, a potent and selective PPAR-β/δ agonist, on tissue injury, caused in a mouse model of SAO shock. IRI of the intestine was caused by clamping the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp, allowing reperfusion for 1 or 6 h. Only 10% of the SAO animals survived the entire 6-h reperfusion period. In a separate set of experiments after 60 min of reperfusion, animals were killed for histological examination and biochemical studies. Administration of GW0742 (0.1 mg/ kg, i.p.), 5 min prior to reperfusion, significantly reduced the (1) mortality rate, (2) histological evidence of gut injury, (3) MPO activity, (4) proinflammatory cytokines (TNF-α, IL-1β), (5) adhesion molecules (ICAM-1, P-selectin), (6) nitrotyrosine formation, (7) NF-κB expression, (8) PAR formation, and (9) apoptosis (Bax, Bcl-2, Fas-L, and TUNEL). Based on these findings, we propose that GW0742 would be useful in the treatment of various I/R diseases.

Original languageEnglish
Pages (from-to)291-301
Number of pages11
JournalJournal of Leukocyte Biology
Volume88
Issue number2
DOIs
Publication statusPublished - Aug 2010

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Keywords

  • Apoptosis
  • MPO activity
  • NF-κB expression
  • Nitrosative stress
  • Proinflammatory cytokines
  • SAO shock

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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