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Am J Physiol Lung Cell Mol Physiol (December 9, 2005). doi:10.1152/ajplung.00422.2005
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Submitted on October 4, 2005
Accepted on December 2, 2005

Effect of adenosine A2A receptor activation in murine models of respiratory disorders

Olivier Bonneau1, Daniel Wyss1, Stephane Ferretti1, Clare Blaydon1, Christopher S Stevenson1, and Alexandre Trifilieff2*

1 Respiratory Diseases Area, Novartis Institute for BioMedical Research, Horsham, United Kingdom
2 Respiratory Diseases Area, Novartis Institute for Biomedical Research, Basel, Switzerland

* To whom correspondence should be addressed. E-mail: alexandre.trilieff{at}novartis.com.

Activation of the adenosine A2A receptor has been postulated as a possible treatment for lung inflammatory diseases such as asthma and COPD. In this report, we have studied the anti-inflammatory properties of the reference A2A agonist CGS 21680, given intranasally at doses of 10 and 100 µg/kg, in a variety of murine models of asthma and COPD. Following an acute ovalbumin challenge of sensitised mice, prophylactic administration of CGS 21680, inhibited the bronchoalveolar lavage fluid inflammatory cell influx but not the airway hyperreactivity to aerosolised methacholine. Following repeated ovalbumin challenges, CGS 21680 given therapeutically, inhibited the bronchoalveolar lavage fluid inflammatory cell influx but had no effect on the allergen-induced bronchoconstriction, the airway hyperreactivity, or the bronchoalveolar lavage fluid mucin levels. As a comparator, budesonide given intranasally at doses of 0.1 to 1 mg/kg fully inhibited all the parameters measured in the latter model. In a lipopolysaccharide-driven model, CGS 21680 had no effect on the bronchoalveolar lavage fluid inflammatory cell influx or TNF-{alpha}, KC and MIP-2 levels, but potently inhibited neutrophil activation, as measured by bronchoalveolar lavage fluid elastase levels. Using a cigarette smoke model of lung inflammation, CGS 21680, did not significantly inhibit bronchoalveolar lavage fluid neutrophil infiltration but reversed the cigarette smoke-induced decrease in macrophage number. Taken together, these results suggest that activation of the A2A receptor would have a beneficial effect by inhibiting inflammatory cell influx and down-regulating inflammatory cell activation in asthma and COPD, respectively.




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