PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse

Carine Delayre-Orthez,Vincent Lagente,Julien Becker,Nelly Frossard,Johan Auwerx,Françoise Pons,Isabelle Guenon

doi:10.1186/1465-9921-6-91

Abstract

BackgroundInflammation 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-α (PPARα) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARα 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 PPARα may play a beneficial role in inflammation and tissue remodeling.MethodsWe have investigated the role of PPARα in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-α (TNF-α), 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 PPARα in this model was studied using both PPARα-deficient mice and mice treated with the PPARα activator, fenofibrate.ResultsUpon intranasal exposure to LPS, PPARα-/- mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-α, KC, MIP-2 and MCP-1, when compared to PPARα+/+ mice. PPARα-/- 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-α, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPARα-/- mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARα mediates the anti-inflammatory effect of fenofibrate.ConclusionUsing both genetic and pharmacological approaches, our data clearly show that PPARα downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARα activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages.

Highlights

Inflammation is a hallmark of acute lung injury and chronic airway diseases
Upon exposure to LPS, both Peroxisome proliferator-activated receptor-α (PPARα)+/+ and PPARα-/- mice displayed a significant increase in total cell, neutrophil and macrophage number, when compared to animals exposed to saline (Figure 1)
Using both genetic and pharmacological approaches, our data clearly showed that PPARα downregulates cell infiltration, chemoattractant production and enhanced matrix metalloproteinases (MMP) activity triggered by LPS in mouse lung

Summary

Introduction

Inflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Agonists for PPARα 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 PPARα may play a beneficial role in inflammation and tissue remodeling. Inflammatory response triggered by LPS is characterized by neutrophil and macrophage recruitment and by the release of chemoattractants including tumor necrosis factor-α (TNF-α), and the CXC and CC chemokines, interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively [2,3,4,5] These inflammatory events reproduce some of the features of the inflammatory response observed during acute lung injury or COPD [1,6]. PPARα agonists were shown to reduce LPS- and cytokine-induced MMP-9 secretion in human monocytes and rat mesangial cells, suggesting that PPARα may play a beneficial role in tissue remodeling [24,25]

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