1 Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have been proposed to regulate inflammation by antagonising the nuclear factor-kB (NF-kB) signalling pathway. We investigated the role of PPARs using synthetic agonists in murine models of airway inflammation, and addressed the possible effect on NF-kB signalling in vitro using a human epithelial cell line, A549. 2 Sensitised BALB/c mice exposed to an aerosol solution of ovalbumin had an increased number of airway eosinophils, neutrophils and lymphocytes. When given intranasally an hour before the aerosol challenge, a PPAR-a (GW 9578) and PPAR-g (GI 262570) selective agonist as well as a dual PPAR-a/g (GW 2331) agonist selectively inhibited allergen-induced bronchoalveolar lavage eosinophil and lymphocyte but not neutrophil influx. In contrast, a PPAR-d agonist (GW 501516) was inactive. 3 When given intranasally an hour before challenge, PPAR-a and PPAR-g selective agonists as well as a dual PPAR-a/g agonist did not inhibit lipopolysaccharide-induced bronchoalveolar lavage neutrophil influx or tumour necrosis factor-a (TNF-a) and KC production. 4 In A549 cells, selective agonists for PPAR-a, -g and -d did not inhibit intracellular adhesion molecule-1 expression following stimulation with proinflammatory cytokines. In addition, IL-8 release and the activation of an NF-kB-responsive reporter gene construct were inhibited only at micromolar concentrations, suggesting that these effects were not PPAR-mediated. 5 Our in vivo data show that agonists of PPAR-a and -g, but not -d, inhibit allergen-induced bronchoalveolar lavage eosinophil and lymphocyte influx. In vitro data suggest that this effect might not be mediated by antagonism of the NF-kB pathway.
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