GW0742, a high-affinity PPAR -beta/delta agonist, inhibits acute lung injury in mice.
Several lines of evidence suggest a biological role for peroxisome proliferator-activated receptor (PPAR) beta/delta in the pathogenesis of a number of diseases. The aim of this study was to investigate the effects of a high-affinity PPAR-beta/delta agonist, GW0742, in a mouse model of carrageenan (CAR)-induced pleurisy. Injection of CAR into the pleural cavity of mice elicited an acute inflammatory response characterized by accumulation of fluid containing a large number of neutrophils (polymorphonuclear leukocytes) in the pleural cavity, infiltration of polymorphonuclear leukocytes in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate, TNF-alpha, and IL-1beta. Furthermore, CAR induced lung apoptosis (Bax and Bcl-2 expression), and nitrotyrosine formation was determined by immunohistochemical analysis of lung tissues. Administration of GW0742 (0.3 mg/kg, i.p. bolus) 30 min before and 30 min after a challenge with CAR caused a reduction in all the parameters of inflammation measured. Thus, based on these findings, we propose that a PPAR-beta/delta agonist such as GW0742 may be useful in the treatment of various inflammatory diseases.
Di Paola
Rosanna
R
IRCCS Centro Neurolesi Bonino-Pulejo, University of Messina, Italy.
Crisafulli
Concetta
C
Mazzon
Emanuela
E
Esposito
Emanuela
E
Paterniti
Irene
I
Galuppo
Maria
M
Genovese
Tiziana
T
Thiemermann
Christoph
C
Cuzzocrea
Salvatore
S
D055371:Acute Lung Injury / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002351:Carrageenan; D020672:I-kappa B Proteins / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D009504:Neutrophils / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D047494:PPAR delta / Q000819:agonists; D048068:PPAR-beta / Q000819:agonists; D010998:Pleurisy / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
D002351:Carrageenan; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D047494:PPAR delta; D048068:PPAR-beta; D019253:Proto-Oncogene Proteins c-bcl-2; D013844:Thiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D051028:bcl-2-Associated X Protein; C000606205:Nfkbia protein, mouse; C002744:3-nitrotyrosine; 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; C496317:Nos2 protein, mouse