PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse -: art. no. 91

Background: Inflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARa have been recently shown to reduce lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, suggesting that PPAR alpha may play a beneficial role in inflammation and tissue remodeling. Methods: We have investigated the role of PPAR alpha in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-alpha (TNF-alpha), keratinocyte derived-chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The role of PPAR alpha in this model was studied using both PPAR alpha-deficient mice and mice treated with the PPAR alpha activator, fenofibrate. Results: Upon intranasal exposure to LPS, PPAR alpha-/- mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-alpha, KC, MIP-2 and MCP-1, when compared to PPAR alpha(+/+) mice. PPAR alpha-/- mice also displayed enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) dose-dependently reduced the increase in neutrophil and macrophage number induced by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this effect was associated with a reduction in TNF-alpha, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPAR alpha-/- mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPAR alpha mediates the anti-inflammatory effect of fenofibrate. Conclusion: Using both genetic and pharmacological approaches, our data clearly show that PPAR alpha downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPAR alpha activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages.