PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the mouse.
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 (PPARalpha) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARalpha 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 PPARalpha may play a beneficial role in inflammation and tissue remodeling. METHODS: We have investigated the role of PPARalpha 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 PPARalpha in this model was studied using both PPARalpha-deficient mice and mice treated with the PPARalpha activator, fenofibrate. RESULTS: Upon intranasal exposure to LPS, PPARalpha-/- 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 PPARalpha+/+ mice. PPARalpha-/- 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. PPARalpha-/- mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARalpha mediates the anti-inflammatory effect of fenofibrate. CONCLUSION: Using both genetic and pharmacological approaches, our data clearly show that PPARalpha downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARalpha activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages.