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.