Regulation of peroxisome proliferator-activated receptor-alpha expression during lung inflammation.

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is implicated in the control of airway inflammation. However, little is known so far about PPARalpha expression and regulation in the lung. Our aim was to assess PPARalpha 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 PPARalpha activator, fenofibrate, the glucocorticoid, dexamethasone or vehicle was administered to normal mice, to mice exposed to tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) or to ovalbumin (OVA)-sensitized and challenged animals. PPARalpha expression was assessed by quantifying PPARalpha 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-alpha production in bronchoalveolar lavage fluids. PPARalpha 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-alpha or LPS, as well as in animals sensitized and challenged with OVA, that exhibited airway inflammation, PPARalpha 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 PPARalpha was maximal at 4h, whereas TNF-alpha production and cell infiltration peaked at 2 and 24h, respectively. In the lung of mice exposed to LPS or OVA and treated with fenofibrate or dexamethasone, PPARalpha down-regulation was suppressed, while airway inflammation was abolished. Our data showed that PPARalpha is constitutively expressed in mouse lung and down-regulated in response to TNF-alpha or upon acute or allergic airway inflammation. Fenofibrate and dexamethasone upregulated PPARalpha in normal lung and suppressed PPARalpha down-regulation associated with airway inflammation. Taken together, our data show that PPARalpha expression is inversely regulated with lung inflammation.