Effect of adenosine A2A receptor activation in murine models of respiratory disorders.
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.
Bonneau
Olivier
O
Respiratory Diseases Area, Novartis Institutes for BioMedical Research, Horsham, England, UK.
Wyss
Daniel
D
Ferretti
Stephane
S
Blaydon
Clare
C
Stevenson
Christopher S
CS
Trifilieff
Alexandre
A
D000336:Aerosols; D000485:Allergens; D000818:Animals; D016084:Bronchoconstriction; D004195:Disease Models, Animal; D005260:Female; D007958:Leukocyte Count; D016210:Methacholine Chloride / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D012129:Respiratory Function Tests
D000336:Aerosols; D000485:Allergens; D043705:Receptor, Adenosine A2A; D016210:Methacholine Chloride