Elevated adenosine levels in the lungs and exhaled breath of asthmatics, with further increases following antigen challenge, suggests that this ubiquitous mediator may contribute to the pathophysiology of asthma. Many of the effects of adenosine in the asthmatic lung are mast cell-dependent. Adenosine has both pro- and anti-inflammatory effects on mast cells, due to the expression of multiple adenosine receptors on the cell surface, each capable of activating very different intracellular signaling pathways. In this proposal we will test the hypothesis that both pro- and anti-inflammatory signals are transmitted to the mast cell by adenosine via the activation of distinct cell-surface receptors, and that engagement of these receptors by adenosine influences AHR, inflammatory cell influx, and airway remodeling.
In aim 1 we will investigate the pro- inflammatory role of A3 receptors on mast cells in AHR, airway inflammation, and remodeling.
In aim 2 we will investigate the capacity of agonist-induced activation of Gs-coupled adenosine receptors to limit AHR, airway inflammation, and remodeling.
In aim 3 we will investigate constitutive activity of the A2B receptor. For all aims we will conduct in vitro experiments with human mast cells as well as mechanistic in vivo experiments using a series of models lacking adenosine receptors on mast cells. Completion of these aims will define pro- vs. anti-inflammatory signaling pathways on the mast cell, and identify the mechanisms by which adenosine- induced mast cell activation contributes to the cardinal features of asthma.
. Asthma is a common chronic disease affecting approximately 10% of people in the United States. A better understanding of the inflammatory mediators involved in this disease, such as adenosine, will help identify new avenues of therapy, leading to better treatments for asthma.
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