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

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is implicated in the control of airway inflammation. However, little is known so far about PPAR alpha expression and regulation in the lung. Our aim was to assess PPAR alpha 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 PPAR alpha 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. PPAR alpha expression was assessed by quantifying PPAR alpha 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. PPAR alpha 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, PPAR alpha 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 PPAR alpha was maximal at 4 h, whereas TNF-alpha 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, PPAR alpha down-regulation was suppressed, while airway inflammation was abolished. Our data showed that PPAR alpha 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 PPAR alpha in normal lung and suppressed PPAR alpha down-regulation associated with airway inflammation. Taken together, our data show that PPARalpha expression is inversely regulated with lung inflammation. (C) 2007 Elsevier Ltd. All rights reserved.