The purine nucleoside adenosine is a biologically active extracellular signaling molecule that is formed at sites of metabolic stress associated with trauma and sepsis. Adenosine can bind to one or more of four cell surface receptors (A1, A2A, A2B, and A3) through which it exerts varying immunomodulatory effects. We have discovered that stimulation of A2A receptors with endogenous adenosine contributes to the mortality of mice subjected to a septic insult. This decreased survival of mice caused by A2A receptor stimulation was tightly associated with a capacity of A2A receptor activation to increase bacterial burden, to augment immune cell apoptosis, and to increase production of inflammatory cytokines. Further work performed suggests that adenosine has a more complex role in the pathophysiology of sepsis. Specifically, depending on which receptors are activated, adenosine differentially modulates immune function. For example, activation of A2B receptors by endogenous adenosine decreases the production of inflammatory cytokines in mice suffering from sepsis. Thus to better understand the complex regulatory pathways of the adenosine receptor system in sepsis, we propose the following highly integrated Specific Aims:
Aim 1 : Elucidate the role and relative importance of A1, A2A, A2B and A3 adenosine receptors in regulating immunity during sepsis.
Aim 2 : Elucidate the receptors and intracellular signaling pathways that mediate the modulatory effects of adenosine on the transcription and secretion of cytokines by macrophages stimulated with Gram-negative and Gram-positive bacteria. New knowledge about the control of septic immunity by distinct adenosine receptors could lead to the identification of novel pharmacological approaches for ameliorating the course of disease and preventing death in sepsis.

Public Health Relevance

By elucidating how adenosine receptors modulate immune and organ function during sepsis, we can utilize this information to develop new pharmacologic approaches targeting adenosine receptors to treat patients suffering from sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM066189-07
Application #
7807203
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2002-07-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
7
Fiscal Year
2010
Total Cost
$271,814
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Surgery
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
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