A₃ adenosine receptor signaling contributes to airway inflammation and mucus production in adenosine deaminase-deficient mice

Adenosine signaling has been implicated in chronic lung diseases such as asthma and chronic obstructive pulmonary disease; however, the specific roles of the various adenosine receptors in processes central to these disorders are not well understood. In this study, we have investigated the role(s) of the A ₃ adenosine receptor in adenosine-dependent pulmonary inflammation observed in adenosine deaminase (ADA)-deficient mice. The A₃ receptor (A₃R) was found to be expressed in eosinophils and mucusproducing cells in the airways of ADA-deficient mice. Treatment of ADA-deficient mice with MRS 1523, a selective A₃R antagonist, prevented airway eosinophilia and mucus production. Similar findings were seen in the lungs of ADA/A ₃ double knockout mice. Although eosinophils were decreased in the airways of ADA-deficient mice following antagonism or removal of the A ₃R, elevations in circulating and lung interstitial eosinophils persisted, suggesting signaling through the A₃R is needed for the migration of eosinophils into the airways. These findings identify an important role for the A₃R in regulating lung eosinophilia and mucus production in an environment of elevated adenosine.