Regulation of peroxisome proliferator-activated receptor-α expression during lung inflammation

Peroxisome proliferator-activated receptor-α (PPARα) is implicated in the control of airway inflammation. However, little is known so far about PPARα expression and regulation in the lung. Our aim was to assess PPARα expression in the lung from normal mice, as well as to investigate its regulation during airway inflammation or in response to anti-inflammatory agents. The PPARα activator, fenofibrate, the glucocorticoid, dexamethasone or vehicle was administered to normal mice, to mice exposed to tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) or to ovalbumin (OVA)-sensitized and challenged animals. PPARα expression was assessed by quantifying PPARα mRNA levels using real-time quantitative PCR after reverse-transcription of total lung RNA. Airway inflammation was evaluated by determining total and differential cell counts, as well as TNF-α production in bronchoalveolar lavage fluids. PPARα mRNA was found at significant levels in the lung from normal mice. This expression was increased by 65% (p<0.05) and 55% (p<0.05) in animals treated with fenofibrate and dexamethasone, respectively. In mice exposed to TNF-α or LPS, as well as in animals sensitized and challenged with OVA, that exhibited airway inflammation, PPARα mRNA was decreased by 60% (p<0.05), 43% (p<0.05) and 50% (p<0.05), respectively. In mice exposed to LPS, down-regulation of PPARα was maximal at 4 h, whereas TNF-α production and cell infiltration peaked at 2 and 24 h, respectively. In the lung of mice exposed to LPS or OVA and treated with fenofibrate or dexamethasone, PPARα down-regulation was suppressed, while airway inflammation was abolished. Our data showed that PPARα is constitutively expressed in mouse lung and down-regulated in response to TNF-α or upon acute or allergic airway inflammation. Fenofibrate and dexamethasone upregulated PPARα in normal lung and suppressed PPARα down-regulation associated with airway inflammation. Taken together, our data show that PPARalpha expression is inversely regulated with lung inflammation.