GW0742, a selective PPAR-beta/delta agonist, contributes to the resolution of inflammation after gut ischemia/reperfusion injury.
PPARs belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta, and gamma, 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-beta/delta 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-alpha, IL-1beta), (5) adhesion molecules (ICAM-1, P-selectin), (6) nitrotyrosine formation, (7) NF-kappaB 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.
Di Paola
Rosanna
R
IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy.
Esposito
Emanuela
E
Mazzon
Emanuela
E
Paterniti
Irene
I
Galuppo
Maria
M
Cuzzocrea
Salvatore
S
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy*; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015996:Survival Rate; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D010636:Phenols; D013438:Sulfhydryl Compounds
D016207:Cytokines; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds