Asthma is a chronic inflammatory disease of the airways. Over the past 15 years, the number of Americans afflicted with asthma has more than doubled to over 14 million. The factors that predispose individuals to asthma, or lead to its development are actively studied; however, relatively little is known about the factors that govern the chronic nature of this disease. Adenosine is a signaling nucleoside that plays a role in chronic lung diseases such as asthma and chronic obstructive pulmonary diseases (COPD). However, very little is known about the mechanisms by which adenosine may impact these diseases. Adenosine deaminase (ADA) is a purine catabolic enzyme that controls the levels of adenosine in tissues and cells. Mice deficient in ADA develop severe lung inflammation and damage in association with elevated adenosine levels. During the previous funding period of this grant we showed that airway inflammation and remodeling in ADA-deficient lungs was very similar to the inflammation and damage seen in the lungs of asthmatics and COPD patients. Furthermore, we demonstrated that many of the phenotypes seen were due to increases in lung adenosine. The mechanisms by which adenosine directs these changes in the inflamed lung are not clear; however, recent findings have demonstrated that levels of the various adenosine receptors are increased in ADA-deficient lungs and the multifunctional cytokines IL-13 and IL-6 have been found to be upregulated, suggesting that these mediators may impact adenosine-mediated pulmonary phenotypes. Thus, the general hypothesis that will be tested in this proposal is that adenosine receptor signaling impacts chronic lung disease by the regulation of mediator production in the lung.
Four specific aims are designed to address this hypothesis:
Aim 1. Determine the importance of specific adenosine receptors in adenosine dependent lung inflammation and airway remodeling.
Aim 2. Investigate the function of the A3 adenosine receptor on eosinophils.
Aim 3. Examine the regulation and function of IL-13 in adenosine-mediated lung pathologies in ADA-deficient mice.
Aim 4. Examine the regulation and function of IL-6 in adenosine mediated lung pathologies in ADA-deficient mice. These studies will lead to a better understanding of adenosine's impact on the severity of chronic lung diseases such as asthma and COPD, which will help guide the development of novel therapies for their treatment.
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