title: Role of PPAR-delta in the development of zymosan-induced multiple organ failure: an experiment mice study.
abstract: BACKGROUND
  Peroxisome proliferator-activated receptor (PPAR)-beta/delta is a nuclear receptor transcription factor that regulates gene expression in many important biological processes. It is expressed ubiquitously, especially white adipose tissue, heart, muscle, intestine, placenta and macrophages but many of its functions are unknown. Saturated and polyunsaturated fatty acids activate PPAR-beta/delta, but physiological ligands have not yet been identified. In the present study, we investigated the anti-inflammatory effects of PPAR-beta/delta activation, through the use of GW0742 (0,3 mg/kg 10% Dimethyl sulfoxide (DMSO) i.p), a synthetic high affinity ligand, on the development of zymosan-induced multiple organ failure (MOF).
  
  
  METHODS
  Multiple organ failure (MOF) was induced in mice by administration of zymosan (given at 500 mg/kg, i.p. as a suspension in saline). The control groups were treated with vehicle (0.25 ml/mouse saline), while the pharmacological treatment was the administration of GW0742 (0,3 mg/kg 10% DMSO i.p. 1 h and 6 h after zymosan administration). MOF and systemic inflammation in mice was assessed 18 hours after administration of zymosan.
  
  
  RESULTS
  Treatment with GW0742 caused a significant reduction of the peritoneal exudate formation and of the neutrophil infiltration caused by zymosan resulting in a reduction in myeloperoxidase activity. The PPAR-beta/delta agonist, GW0742, at the dose of 0,3 mg/kg in 10% DMSO, also attenuated the multiple organ dysfunction syndrome caused by zymosan. In pancreas, lung and gut, immunohistochemical analysis of some end points of the inflammatory response, such as inducible nitric oxide synthase (iNOS), nitrotyrosine, poly (ADP-ribose) (PAR), TNF- and IL-1as well as FasL, Bax, Bcl-2 and apoptosis, revealed positive staining in sections of tissue obtained from zymosan-injected mice. On the contrary, these parameters were markedly reduced in samples obtained from mice treated with GW0742
  
  
  CONCLUSIONS
  In this study, we have shown that GW0742 attenuates the degree of zymosan-induced non-septic shock in mice.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Galuppo
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.|IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Crisafulli
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cuzzocrea
authors.affiliation: IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.affiliation: The William Harvey Research Institute, Centre for Experimental Medicine, Nephrology and Critical Care, St Bartholomew's, London, UK.|The Royal London School of Medicine and Dentistry, London, UK.
authors.forename: Amar
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: The William Harvey Research Institute, Centre for Experimental Medicine, Nephrology and Critical Care, St Bartholomew's, London, UK.|The Royal London School of Medicine and Dentistry, London, UK.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.|IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea