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Identification of A₃ Receptor- and Mast Cell-Dependent and -Independent Components of Adenosine-Mediated Airway Responsiveness in Mice¹

Stephen L. Tilley^*, Mindy Tsai, Cara M. Williams, Z.-S. Wang, Christopher J. Erikson^*, Stephen J. Galli and Beverly H. Koller^2,*,

^* Department of Medicine, Division of Pulmonary and Critical Care Medicine, and Department of Genetics, University of North Carolina, Chapel Hill, NC 27599; and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305

Adenosine-induced bronchoconstriction is a well-recognized feature of atopic asthma. Adenosine acts through four different G protein-coupled receptors to produce a myriad of physiological effects. To examine the contribution of the A₃ adenosine receptor to adenosine-induced bronchoconstriction and to assess the contribution of mast cells to this process, we quantified airway responsiveness to aerosolized adenosine in wild-type, A₃ receptor-deficient, and mast cell-deficient mice. Compared with the robust airway responses elicited by adenosine in wild-type mice, both A₃-deficient and mast cell-deficient mice exhibited a significantly attenuated response compared with their respective wild-type controls. Histological examination of the airways 4 h after adenosine exposure revealed extensive degranulation of airway mast cells as well as infiltration of neutrophils in wild-type mice, whereas these findings were much diminished in A₃-deficient mice and were not different from those in PBS-treated controls. These data indicate that the airway responses to aerosolized adenosine in mice occur largely through A₃ receptor activation and that mast cells contribute significantly to these responses, but that activation of additional adenosine receptors on a cell type(s) other than mast cells also contributes to adenosine-induced airway responsiveness in mice. Finally, our findings indicate that adenosine exposure can result in A₃-dependent airway inflammation, as reflected in neutrophil recruitment, as well as alterations in airway function.

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