Metabolic consequences of adenosine deaminase deficiency in mice are associated with defects in alveogenesis, pulmonary inflammation, and airway obstruction

Adenosine deaminase (ADA) is a purine catabolic enzyme that manages levels of the biologically active purines adenosine and 2'-deoxyadenosine in tissu es and cells. ADA-deficient mice die at 3 wk of age from severe respiratory distress. This phenotype is progressive and is linked to perturbations in pulmonary purine metabolism. The inflammatory changes found in the lungs of ADA-deficient mice included an accumulation of activated alveolar macropha ges and eosinophils. These changes were accompanied by a pronounced enlarge ment of alveolar spaces and increases in mucus production in the bronchial airways. The alveolar enlargement was found to be due in part to abnormal a lveogenesis. Lowering adenosine and 2'-deoxyadenosine levels using ADA enzy me therapy decreased the pulmonary eosinophilia and resolved many of the lu ng histopathologies. In addition, genetically restoring ADA to the forestom ach of otherwise ADA-deficient mice prevented adenine metabolic disturbance s as well as lung inflammation and damage. These data suggest that disturba nces in purinergic signaling mediate the lung inflammation and damage seen in ADA-deficient mice.