This application focuses on the potential role of adenosine in inflammation in general, and mast cell function in particular. Adenosine has important anti-inflammatory actions, most likely mediated via A2A receptors inhibiting neutrophil activation and adhesion and T-cell activation. In contrast, adenosine also has proinflammatory effects, particularly in the lung. Mice lacking adenosine deaminase express high levels of tissue adenosine and are characterized by chronic lung inflammation and bronchial hyperreactivity. In humans, inhaled adenosine induces bronchoconstriction in asthmatics but not in normals. Mast cells contribute to this effect, and hypersensitivity to inhaled adenosine correlates with indices of lung inflammation. We hypothesize that A2B and/or A3, in contrast to A2A receptors, are responsible for the pro-inflammatory effects of adenosine. In support of this hypothesis, adenosine inhibits mast cells predominantly expressing A2A receptors, and activates mast cells predominantly expressing either A2B or A3 receptors. Furthermore, we found that A2B receptors activate the human mast cell HMC-1, releasing the Th2 cytokines IL-4 and IL- 13, which in turn induce IgE synthesis by B cells. Of interest, both A2A and A2B receptors are often coexpressed in mast cells and other inflammatory cells, but only one of them predominates functionally.
In Specific Aim 1 we will test the hypothesis that inflammatory conditions (hypoxia, Th2 cytokines) modulate the differential expression of adenosine receptors in mast cells, from a predominant A2A to an A2B """"""""proinflammatory"""""""" phenotype, as suggested by preliminary results.
In Specific Aim 2 we will explore intracellular signaling pathways that may explain differential functions of A2A and A2B receptors, and in Specific Aim 3 we will identify the functional domains of the adenosine A2B receptor responsible for such differential coupling. Finally, in Specific Aim 4, we will explore the relevance of adenosine receptor subtypes in an in vivo model of chronic pulmonary inflammation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076306-04
Application #
7331491
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2005-01-01
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$357,938
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zaynagetdinov, Rinat; Ryzhov, Sergey; Goldstein, Anna E et al. (2010) Attenuation of chronic pulmonary inflammation in A2B adenosine receptor knockout mice. Am J Respir Cell Mol Biol 42:564-71
Feoktistov, Igor; Biaggioni, Italo; Cronstein, Bruce N (2009) Adenosine receptors in wound healing, fibrosis and angiogenesis. Handb Exp Pharmacol :383-97
Ryzhov, Sergey; Zaynagetdinov, Rinat; Goldstein, Anna E et al. (2009) Differential role of the carboxy-terminus of the A(2B) adenosine receptor in stimulation of adenylate cyclase, phospholipase Cbeta, and interleukin-8. Purinergic Signal 5:289-98
Ryzhov, Sergey; Solenkova, Nataliya V; Goldstein, Anna E et al. (2008) Adenosine receptor-mediated adhesion of endothelial progenitors to cardiac microvascular endothelial cells. Circ Res 102:356-63
Novitskiy, Sergey V; Ryzhov, Sergey; Zaynagetdinov, Rinat et al. (2008) Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112:1822-31
Ryzhov, Sergey; Zaynagetdinov, Rinat; Goldstein, Anna E et al. (2008) Effect of A2B adenosine receptor gene ablation on adenosine-dependent regulation of proinflammatory cytokines. J Pharmacol Exp Ther 324:694-700
Ryzhov, Sergey; Novitskiy, Sergey V; Zaynagetdinov, Rinat et al. (2008) Host A(2B) adenosine receptors promote carcinoma growth. Neoplasia 10:987-95
Ryzhov, Sergey; Zaynagetdinov, Rinat; Goldstein, Anna E et al. (2008) Effect of A2B adenosine receptor gene ablation on proinflammatory adenosine signaling in mast cells. J Immunol 180:7212-20
Ryzhov, Sergey; McCaleb, Jennifer L; Goldstein, Anna E et al. (2007) Role of adenosine receptors in the regulation of angiogenic factors and neovascularization in hypoxia. J Pharmacol Exp Ther 320:565-72
Ryzhov, Sergey; Goldstein, Anna E; Biaggioni, Italo et al. (2006) Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. Mol Pharmacol 70:727-35