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.

Public Health Relevance

. 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071802-07
Application #
7882355
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2002-12-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
7
Fiscal Year
2010
Total Cost
$370,000
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Sharifi-Sanjani, Maryam; Zhou, Xueping; Asano, Shinichi et al. (2013) Interactions between A(2A) adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia. Am J Physiol Heart Circ Physiol 304:H1294-301
Hua, Xiaoyang; Chason, Kelly D; Jania, Corey et al. (2013) Gs-coupled adenosine receptors differentially limit antigen-induced mast cell activation. J Pharmacol Exp Ther 344:426-35
Brickey, Willie J; Neuringer, Isabel P; Walton, William et al. (2012) MyD88 provides a protective role in long-term radiation-induced lung injury. Int J Radiat Biol 88:335-47

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