Modulation of LPS-induced pulmonary neutrophil infiltration and cytokine production by the selective PPARbeta/delta ligand GW0742.
OBJECTIVE
To define the anti-inflammatory effects of PPARbeta/delta activation by use of the selective PPARbeta/delta ligand (GW0742) in a model of lipopolysaccharide (LPS)-induced pulmonary inflammation.


METHODS
Male BALB/c mice were pretreated for three days with the PPARbeta/delta agonist, GW0742, prior to induction of LPS-mediated pulmonary inflammation. Bronchial alveolar lavage fluid (BALF) was analyzed for inflammatory cell influx and for levels of pro-inflammatory mediators. BALF-derived inflammatory cells were also collected for mRNA analysis.


RESULTS
Pretreatment with GW0742 resulted in a significant decrease in leukocyte recruitment into the pulmonary space. Protein and mRNA levels of the pro-inflammatory cytokines IL-6, IL-1beta and TNFalpha in BALF were found to be significantly decreased in GW0742-treated animals (30 mg/kg). A significant decrease in granulocyte macrophage-colony stimulating factor (GM-CSF), a major regulator of neutrophil chemotaxis (via its downstream actions on TNFalpha and other cytokines/chemokines), activation and survival, was also noted in the BALF levels of GW0742-treated animals.


CONCLUSIONS
The present study demonstrates that activation of PPARbeta/delta attenuates the degree of inflammation in a model of LPS-induced pulmonary inflammation and may therefore represent a novel therapeutic approach for the treatment of inflammation-mediated pathologies.
Haskova
Z
Z
Biopharmaceutical Center for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA, USA.
Hoang
B
B
Luo
G
G
Morgan
L A
LA
Billin
A N
AN
Barone
F C
FC
Shearer
B G
BG
Barton
M E
ME
Kilgore
K S
KS
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007249:Inflammation; D007962:Leukocytes / Q000187:drug effects; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism*; D048068:PPAR-beta / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology; D010636:Phenols; D013438:Sulfhydryl Compounds
D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008024:Ligands; D008070:Lipopolysaccharides; 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