Adenosine-dependent airway inflammation and hyperresponsiveness in partially adenosine deaminase-deficient mice

Adenosine is a signaling nucleoside that is elevated in the lungs of asthma tics. We have engineered a mouse model that has elevated levels of adenosin e as a result of the partial expression of the enzyme that metabolizes aden osine, adenosine deaminase (ADA). Mice with lowered levels of ADA enzymatic activity were generated by the ectopic expression of an ADA minigene in th e gastrointestinal tract of otherwise ADA-deficient mice. These mice develo ped progressive lung inflammation and damage and died at 4-5 mo of age from respiratory distress. Associated with this phenotype was a progressive inc rease in lung adenosine levels. Examination of airway physiology at 6 wk of age revealed alterations in airway hyperresponsiveness. This was reversed following the lowering of adenosine levels using ADA enzyme therapy and als o through the use of the adenosine receptor antagonist theophylline, implic ating both the nucleoside and its receptors in airway physiological alterat ions. All four adenosine receptors were expressed in the lungs of both cont rol and partially ADA-deficient mice. However, transcript levels for the A( 1), A(2B), and A(3) adenosine receptors were significantly elevated in part ially ADA-deficient lungs. There was a significant increase in alveolar mac rophages, and monocyte chemoattractant protein-3 was found to be elevated i n the bronchial epithelium of these mice, which may have important implicat ions in the regulation of pulmonary inflammation and airway hyperresponsive ness. Collectively, these findings suggest that elevations in adenosine can directly impact lung inflammation and physiology.