Role of PPAR-delta in the development of zymosan-induced multiple organ failure: an experiment mice study.
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.
Galuppo
Maria
M
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Di Paola
Rosanna
R
IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
Mazzon
Emanuela
E
IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
Genovese
Tiziana
T
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.|IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
Crisafulli
Concetta
C
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Paterniti
Irene
I
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Cuzzocrea
Elisabetta
E
IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
Bramanti
Placido
P
IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.
Kapoor
Amar
A
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.
Thiemermann
Christoph
C
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.
Cuzzocrea
Salvatore
S
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.|IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy.