title: Peroxisome proliferator-activated receptor β/δ agonist GW0742 ameliorates cerulein- and taurocholate-induced acute pancreatitis in mice.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily. PPARs activation has a profound impact on the local immune response with consequences affecting the progression of chronic inflammatory diseases. Relatively little is known on the role of PPAR-β/δ in the regulation of inflammatory responses. The aim of the present study was to evaluate the influence of PPAR-β/δ receptor in a model of edematous pancreatitis induced in mice by administration of cerulein at supramaximal doses, as well as in necrohemorrhagic model induced by intraductal administration of sodium taurocholate (STC).
  
  
  METHODS
  Mice were treated with cerulein (50 μg/kg) or STC (5%). GW0742 (0.3 mg/kg) was intraperitoneally administered 1 and 6 hours after cerulein injection or was injected 2 hours before STC infusion. The pancreas and exopancreatic organs were carefully removed for microscopic examination. Pancreatic weight, serum amylase, lipase, tumor necrosis factor-α and interleukin-1β levels, as well as cytokines, adhesion molecules, nitrotyrosine, poly (ADP-ribose), inducible nitric oxide, FAS ligand, Bax, Bcl-2 expression by immunohistochemistry, and myeloperoxidase activity of the pancreas were assayed. Moreover, the involvement of nuclear factor-κB pathway was investigated by Western blot analysis.
  
  
  RESULTS
  Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration and apoptosis, and elevated serum levels of amylase and lipase. Taurocholate challenge caused a clear increase in serum amylase, neutrophil infiltration, and tissue damage in the pancreas. Tissue and inflammatory changes in the pancreata were significantly less in GW0742 group than in cerulein or STC groups. In addition, the pancreatic water content was reduced in mice treated with PPAR-β/δ agonist. In the mild pancreatitis, GW0742 was also able to decrease the expression of proinflammatory cytokines and enzymes, as well as of proteins involved in apoptosis and nuclear factor-Kappa B pathway.
  
  
  CONCLUSIONS
  GW0742 attenuated pancreatic damage in 2 different experimental models of pancreatitis in mice.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Luisa
authors.initials: L
authors.lastname: Riccardi
authors.forename: Maria
authors.initials: M
authors.lastname: Galuppo
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cappellani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D002108:Ceruletide / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008049:Lipase / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000473:pathology; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D013656:Taurocholic Acid / Q000009:adverse effects*; D013844:Thiazoles / Q000627:therapeutic use*; D013997:Time Factors; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D000681:Amylases; D015815:Cell Adhesion Molecules; D002108:Ceruletide; D008049:Lipase; D047494:PPAR delta; D048068:PPAR-beta; D013656:Taurocholic Acid; 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