PPAR-gamma agonists as therapy for diseases involving airway neutrophilia.
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor super-family. Previously, the present authors have shown that PPAR-gamma 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-gamma agonists have been shown to be clinically effective for the treatment of type II diabetes, suggesting that any benefit of peroxisome proliferator-activated receptor-gamma ligands in the progression of respiratory diseases, which may involve airway neutrophilia, could be explored relatively quickly.
Respiratory Pharmacology Group, Cardiothoracic Surgery, The National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.
M A
MA
Birrell
H J
HJ
Patel
K
K
McCluskie
S
S
Wong
T
T
Leonard
M H
MH
Yacoub
M G
MG
Belvisi
D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors*; D011336:Probability; D012016:Reference Values; D000077154:Rosiglitazone; D012680:Sensitivity and Specificity; D045162:Thiazolidinediones / Q000494:pharmacology*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D047492:Peroxisome Proliferator-Activated Receptors; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D020780:Matrix Metalloproteinase 9