Asthma is an inflammatory disease of the airways. In the U.S., 13 percent of children and 6 percent of adults suffer from asthma and 1 percent of health care cost are devoted to asthma treatment. The disease is typified by the infiltration and activation of immune cells in the lung, followed by airway damage and occlusion. Many factors trigger asthma; however, the mechanisms leading to inflammation and airway damage are not well understood. Adenosine is a signaling molecule that can elicit many physiological responses by engaging G- protein membrane associated receptors. Adenosine signaling has long been implicated in asthma; however, an in vivo understanding of the cellular sites of action and receptor subtypes involved remains unclear. This is due in part to the absence of an adequate genetic animal model with which to study the role of adenosine signaling in inflammatory asthma. Adenosine deaminase (ADA) is an essential enzyme of purine metabolism and functions to regulate adenosine levels in tissues and cells. We have used a two stage genetic engineering strategy to generate ADA deficient mice and show that adenosine levels are markedly elevated in the lungs of these mice. ADA deficient mice develop severe pulmonary insufficiency, and show histopathological evidence for the development of asthma including massive infiltration of inflammatory cells into the lung and severe airway damage. This suggests that ADA deficient mice are a genetic model for inflammatory asthma. Furthermore, genetically preventing adenosine accumulation in the lung prevented signs of inflammation and lung damage, leading to the hypothesis that adenosine signaling is playing a key role in the inflammation and lung damage seen in ADA deficient mice, and that these mice will serve as a useful genetic model for studying the role of adenosine signaling in asthma.
Four specific aims are proposed to test this hypothesis: 1. Characterize the asthma phenotype seen in ADA deficient mice. 2. Assess the role of adenosine in the inflammation and lung damage seen in ADA deficient mice. 3. Monitor the ontogeny and severity of airway damage and perturbations in adenosine signaling following the removal of ADA enzyme therapy. 4. Identify and characterize the adenosine receptor subtypes involved in the inflammation and airway damage seen in ADA deficient mice.
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