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

Bonneau, Olivier and Wyss, Daniel and Ferretti, Stephane Raymond and Blaydon, Clare and Stevenson, Christopher and Trifilieff, Alexandre (2006) Effect of adenosine A2A receptor activation in murine models of respiratory disorders. American Journal of Physiology. Lung cellular and molecular physiology, 290 (5). L1036-L1043. ISSN 1040-0605

Abstract

Activation of the adenosine A(2A) receptor has been postulated as a possible treatment for lung inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). In this report, we have studied the anti-inflammatory properties of the reference A(2A) agonist CGS-21680, given intranasally at doses of 10 and 100 microg/kg, in a variety of murine models of asthma and COPD. After an acute ovalbumin challenge of sensitized mice, prophylactic administration of CGS-21680 inhibited the bronchoalveolar lavage fluid inflammatory cell influx but not the airway hyperreactivity to aerosolized methacholine. After 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 0.1-1 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, keratinocyte chemoattractant, and macrophage inflammatory protein-2 levels, but potently inhibited neutrophil activation, as measured by bronchoalveolar lavage fluid elastase levels. With the use of 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. Together, these results suggest that activation of the A(2A) receptor would have a beneficial effect by inhibiting inflammatory cell influx and downregulating inflammatory cell activation in asthma and COPD, respectively.

Item Type: Article
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Keywords: chronic obstructive pulmonary disorder therapies; anti-asthmatic agents; animal models
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Date Deposited: 14 Dec 2009 13:59
Last Modified: 31 Jan 2013 01:16
URI: https://oak.novartis.com/id/eprint/469

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