GW0742, a high affinity PPAR-β/δ agonist reduces lung inflammation induced by bleomycin instillation in mice.
Peroxisome Proliferator-Activated Receptor β/δ belongs to a family of ligand-activated transcription factors. Recent data have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target. Moreover, although its role in acute inflammation remains unclear, being the nuclear receptor PPAR β/δ widely expressed in many tissues, including the vascular endothelium, we assume that the infiltration of PMNs into tissues, a prominent feature in inflammation, may also be related to PPAR β/δ. Mice subjected to intratracheal instillation of bleomycin (BLEO, 1 mg/kg), a glycopeptide produced by the bacterium Streptomyces verticillus, develop lung inflammation and injury characterized by a significant neutrophil infiltration and tissue oedema. Therefore, the aim of this study is to investigate the effects of GW0742, a synthetic high affinity PPAR β/δ agonist, and its possible role in preventing the advance of inflammatory and apoptotic processes induced by bleomycin, that long-term leads to the appearance of pulmonary fibrosis. Our data showed that GW0742-treatment (0.3 mg/Kg, 10 percent DMSO, i.p.) has therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters detected by measurement of: 1) cytokine production; 2) leukocyte accumulation, indirectly measured as decrease of myeloperoxidase (MPO) activity; 3) IkBα degradation and NF-kB nuclear translocation; 4) ERK phosphorylation; 5) stress oxidative by NO formation due to iNOS expression; 6) nitrotyrosine and PAR localization; 7) the degree of apoptosis, evaluated by Bax and Bcl-2 balance, FAS ligand expression and TUNEL staining. Taken together, our results clearly show that GW0742 reduces the lung injury and inflammation due to the intratracheal BLEO--instillation in mice.
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
M
M
Galuppo
R
R
Di Paola
E
E
Mazzon
E
E
Esposito
I
I
Paterniti
A
A
Kapoor
C
C
Thiemermann
S
S
Cuzzocrea
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000633:toxicity; D053583:Interleukin-1beta / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D047494:PPAR delta / Q000819:agonists*; D048068:PPAR-beta / Q000819:agonists*; D011014:Pneumonia / Q000188:drug therapy*; D013844:Thiazoles / Q000627:therapeutic use*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D010636:Phenols; D013438:Sulfhydryl Compounds
D001761:Bleomycin; D053583:Interleukin-1beta; D009569:Nitric Oxide; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; 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