Adenosine is a signaling nucleoside that impacts cellular physiology by binding G-protein coupled receptors on the surface of target cells. There is mounting evidence that adenosine signaling plays an important role in lung inflammation and damage characteristic of asthma, yet the signaling mechanisms and cell types involved are not well understood. Nor is it known what role adenosine signaling plays in lung development. We have taken a genetic approach to study the role of adenosine signaling in lung development and the onset of inflammatory responses characteristic of asthma. To this end, we generated mice deficient in the purine catabolic enzyme adenosine deaminase (ADA). ADA is responsible for controlling the levels of adenosine in tissues and cells, and ADA deficient mice consequently exhibit elevated levels of adenosine in many tissues, including the lung. ADA deficient mice develop respiratory disease early in life, characterized by a significant lung eosinophilia followed by smooth muscle thickening, epithelial damage, and death of the animal by three weeks of age. This inflammation and damage is dependent on elevated levels of adenosine in that the condition is rapidly reversed following the removal of adenosine by ADA enzyme therapy. These animals will provide an opportunity to study the role of adenosine signaling in asthma and to investigate the influence of environmental factors in this genetic model. Furthermore, recent findings suggest that the lungs of ADA deficient mice are damaged prenatally in association with elevated adenosine levels, leading to the hypothesis that aberrant adenosine signaling in the prenatal and neonatal lung of ADA deficient mice predisposes the lung to inflammation and damage.
Four specific aims are designed to test this hypothesis: 1. Determine the nature and ontogeny of the lung inflammation and damage seen in prenatal and neonatal ADA deficient mice. 2. Determine if the changes in prenatal and neonatal ADA deficient lungs are dependent on adenosine. 3. Assess the cell type specific expression of adenosine receptors in normal and ADA deficient prenatal and neonatal lungs. 4. Evaluate acute and long-term changes of airway function in ADA deficient mice as well as ADA deficient mice exposed to environmental challenges.
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