078 Peroxisome proliferator-activated receptor-alpha decreases airway inflammation in allergen-sensitized and challenged mice exposed to lipopolysaccharide

Abstract

Our previous works showed that peroxisome proliferator-activated receptor-a (PPARα) downregulated airway eosi-nophilic inflammation induced by allergen in sensitized mice [1]. However, inflammation associated with severe asthma involves mixed eosinophil and neutrophil infiltrate and increased levels of IL-5, IL-8 and other inflammatory cell chemoattractants. Concomitant exposure to allergen and lipopolysaccharides (LPS) reproduces some features of this inflammatory response in sensitized mice [2]. We have therefore addressed the anti-inflammatory activity of PPARα in allergen-sensitized and challenged mice exposed to LPS. Ovalbumin (OA)-sensitized wild-type (PPARa +/+ ) vs homozygous knockout (PPARa) mice, as well as OA-sensitized C57BL/6 mice treated with the PPARα agonist, fenofibrate (15 mg/day), were challenged by intranasal instillation of OA in the presence of 100 ng LPS. Airway inflammation was assessed by quantification of cell number and chemoattractants in bronchoal-veolar lavage fluid (BALF). Upon challenge with OA in the presence of LPS, PPARα -/- mice exhibited greater eosinophil, neutrophil and macrophage number (5.6-, 2.3- and 3.1- fold, respectively, p < 0.05) in BALF, when compared to PPARa +/+ animais. PPARα-/- mice dis-played also increased levels of IL-5 (3.3-fold, p < 0.01), MIP-2 (4.3-fold, p < 0.05) and MCP-1 (4.3-fold, p < 0.01). Conversely, fenofibrate markedly reduced the increase in eosinophil, neutrophil and macrophage number (by 92%, 92% and 71%, respectively, p < 0.001) induced by co-exposure to allergen and LPS in OA-sensitized C57BL/6 mice. Reduction in cell number was associated with decreases in IL-5 (54.5%, p < 0.001), MIP-2 (55%, p < 0.05) and MCP-1 (83.5%, p < 0.05). All together, our data provide evidence that PPARα reduces the mixed inflammatory cell infiltrate and the che-moattractant production induced by co-exposure to allergen and LPS in sensitized mice. This suggests that PPARα activation may represent an effective therapeutic approach in severe asthma.