PPARα downregulates airway inflammation induced by lipopolysaccharide in the mouse

Respiratory Research

Françoise Pons³  Nelly Frossard³  Johan Auwerx¹  Vincent Lagente²  Isabelle Guenon²  Julien Becker³  Carine Delayre-Orthez³ 

[1] Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/Inserm/ULP, Illkirch, France;INSERM U620, Faculté des Sciences Pharmaceutiques, Université de Rennes 1, Rennes, France;EA 3771, Inflammation et environnement dans l'asthme, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg I, Illkirch, France

关键词: mouse;    matrix metalloproteinase;    macrophage;    neutrophil;    inflammation;    lipopolysaccharide;    PPARα;   

Others  :  1227254
DOI  :  10.1186/1465-9921-6-91

 received in 2005-01-26, accepted in 2005-08-09,  发布年份 2005

【 摘 要 】

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-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.

Methods

We 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.

Results

Upon 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.

Conclusion

Using 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.

【 授权许可】

   
2005 Delayre-Orthez et al; licensee BioMed Central Ltd.

【 图 表 】

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