Role of Adenosine in Allergic Lung Disease

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DESCRIPTION (provided by applicant): Adenosine has become increasingly recognized as a contributor to the pathogenesis of asthma through its effects on airway tone and airway inflammation. Adenosine acts through four distinct cell surface receptors, however, the specific receptor(s) through which adenosine acts to contribute to asthma pathogenesis is largely unknown. The hypothesis that will be tested in this proposal is that adenosine contributes to both the airway tone and airway inflammation in asthma through identifiable cell surface receptors, and that inactivation of these receptors will influence the degree of bronchoconstriction and airway inflammation. We have chosen to test the hypothesis-utilizing mouse in which each adenosine receptor has been inactivated by gene targeting. We propose to carry out three specific aims to test our hypothesis. First, we will determine the adenosine receptors and cell types mediating the bronchoconstrictor effects of adenosine in the murine airway. Second, we will determine the adenosine receptors responsible for the pro- and anti-inflammatory effects of adenosine in allergic lung inflammation using the ovalbumin asthma model. Finally, we will determine the specific cell types contributing to adenosine-induced modulation of allergic inflammation. The full therapeutic potential of adenosine receptor blockade has not been exploited due to this complex physiology involving multiple adenosine receptors with diverse and sometimes opposing physiological effects. This proposal seeks to better define the pathophysiology of adenosine, acting through each receptor, in an animal model of asthma, so that a more rational exploitation of these receptors with selective pharmacological tools can be investigated in patients with asthma.