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PPAR- agonists as therapy for diseases involving airway neutrophilia

¹ Respiratory Pharmacology Group, Cardiothoracic Surgery, The National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK. ² Glaxosmithkline, Respiratory and Inflammatory Centre of Excellence for Drug Discovery, King of Prussia, PA, USA

CORRESPONDENCE: M.G. Belvisi, Respiratory Pharmacology, Cardiothoracic Surgery, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, SW3 6LY, UK. Fax: 44 2073518173. E-mail: m.belvisi@imperial.ac.uk

Keywords: Colony stimulating factors, murine, neutrophils, peroxisome proliferator-activated receptors

Received: August 28, 2003
Accepted March 14, 2004

This work was supported by the Harefield Research Foundation and a grant from the Clinical Research Committee, Royal Brompton and Harefield Hospital Trust.

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor superfamily. Previously, the present authors have shown that PPAR- agonists inhibit the release of inflammatory cell survival factors and induce apoptosis in vitro. The aim of this study was to determine the effect of two structurally different PPAR agonists in an in vivo model of lipopolysaccharide (LPS)-induced airway inflammation.

Mice were treated with PPAR agonists, rosiglitazone or SB 219994, prior to exposure to aerosolised LPS, and the extent of airway inflammation was assessed 3 h later.

In these experiments, the PPAR ligands inhibited LPS-induced airway neutrophilia and associated chemoattractants/survival factors (keratinocyte-derived chemokine and granulocyte-colony stimulating factor) in the mouse lung.

The present authors postulate that if a peroxisome proliferator-activated receptor agonist has the same effect in man, and neutrophils are important in the progression of respiratory diseases, such as chronic obstructive pulmonary disease, then this class of compounds could be a potential therapy. Furthermore, several peroxisome proliferator-activated receptor- agonists have been shown to be clinically effective for the treatment of type II diabetes, suggesting that any benefit of peroxisome proliferator-activated receptor- ligands in the progression of respiratory diseases, which may involve airway neutrophilia, could be explored relatively quickly.

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