The adenosine A_2B receptor (A_2BR) has a wide tissue distribution that includes fibroblasts, endothelial and epithelial cells. The recent generation of an A_2BR^-/- mouse constructed with a -galactosidase (-gal) reporter gene under control of the endogenous promoter has provided a valuable tool to quantify A_2BR promoter activity (29). To determine the sites of expression of the A_2B receptor in the mouse lung, histologic and flow-cytometric analysis of -galactosidase reporter gene expression in various lung cell populations was performed. The major site of A_2BR promoter activity was found to be the type II alveolar epithelial cells (AECs), identified by co-expression of pro-surfactant protein C, with relatively less expression in alveolar macrophages, bronchial epithelial cells, and cells of the vasculature. Highly purified type II alveolar epithelial cells were prepared by fluorescence-activated sorting of eGFP-positive cells from transgenic mice expressing eGFP under control of the surfactant protein C promoter (21). The type II cells expressed 89-fold higher A_2BR mRNA than pulmonary leukocytes, and the A_2BR was shown to be functional, as treatment of purified type II AECs with the non-specific adenosine receptor agonist, 5'-N-ethylcarboxamidoadenosine (NECA) induced an increase in intracellular cAMP greater that the beta-adrenergic agonist, isoproterenol, that was inhibited completely following treatment by ATL-802, a novel, highly potent (Ki = 8.6 nM) and selective (>900 fold over other adenosine receptor subtypes) antagonist of the mouse A_2BR.