ROLE OF ENDOGENOUS AND EXOGENOUS LIGANDS FOR THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR alpha IN THE DEVELOPMENT OF BLEOMYCIN-INDUCED LUNG INJURY.
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous the PPAR-alpha ligand on the development of lung injury caused by bleomycin administration. Lung injury was induced in PPAR-alpha wild-type (WT) mice and PPAR-alpha knockout (KO) mice by intratracheal administration of bleomycin. An increase of immunoreactivity to poly-ADP-ribose, TNF-alpha, and IL-1 beta, as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated PPAR-alpha WT mice. The absence of a functional PPAR-alpha gene in PPAR-alpha KO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alpha WT with WY-14643 (1 mg/kg daily) significantly reduced the degree of lung injury, the rise in myeloperoxidase activity, and the increase in staining (immunohistochemistry) for poly-ADP-ribose, TNF-alpha, and IL-1 beta caused by bleomycin administration. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of lung injury induced by bleomycin in the mice. Therefore, we propose that the PPAR-alpha ligand may be useful in the treatment of lung injury.
Genovese
Tiziana
T
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
Mazzon
Emanuela
E
Di Paola
Rosanna
R
Muià
Carmelo
C
Crisafulli
Concetta
C
Caputi
Achille P
AP
Cuzzocrea
Salvatore
S
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity*; D001761:Bleomycin / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D008024:Ligands; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists* / Q000172:deficiency / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000008:administration & dosage*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000008:administration & dosage*
D000903:Antibiotics, Antineoplastic; D008024:Ligands; D047493:PPAR alpha; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D001761:Bleomycin; C006253:pirinixic acid