Adenosine A(3) receptor expression and function in eosinophils

The A(3) adenosine receptor is widely expressed in human tissues with the most abundant expression in the lung and liver, but the-predominant cellular localization and functions of this receptor in humans are unknown. Since adenosine influences the activation of circulating and resident inflammatory cells within the lung and leads to exaggerated airway narrowing in individuals with inflammatory airway disorders, we hypothesized that A(3) receptor gene expression is localized to inflammatory cells and that gene expression is upregulated in airway inflammation. Lung and airway tissue were obtained at thoracotomy from nonsmoking subjects and subjects with inflammatory airway disorders associated with tobacco smoke or asthma. In situ hybridization identified A(3) receptors in mesenchymal cells and eosinophils within the lamina propria of the airways and the adventitia of blood vessels, but not in mast cells. A(3) receptor transcripts were highly expressed in peripheral blood eosinophils purified from atopic donors (6.36 +/- 0.60 pg/ug total RNA) in comparison with neutrophils (0.26 +/- 0.06 pg/ug) or mononuclear cells (0.9 +/- 0.15 pg/ug). Mean A(3) receptor transcript abundance was greater in lung tissue from subjects with airway inflammation (0.33 +/- 0.04 pg/ug total RNA) than in normal lung (0.24 +/- 0.03 pg/ug total RNA, P = 0.035). The A(3) receptor agonist N-6-(4-amino-3-iodobenzyl)adenosine dose-dependently inhibited platelet activating factor-induced eosinophil chemotaxis to a maximum of 41%. This inhibitory effect was completely abolished by addition of the A(3) receptor selective antagonist 3-(3-iodo-4-aminobenzyl)-8-(4-oxyacetate)phenyl-1-propylxanthine. We conclude that A(3) receptors are primarily expressed on eosinophils in human lung, where they mediate inhibition of eosinophil chemotaxis. Specific A(3) receptor ligands may be useful agents in the treatment of eosinophil-dependent diseases such as asthma and rhinitis.