[Frontiers in Bioscience 10, 2548-2565, September 1, 2005]

ADVANCES IN UNDERSTANDING ADENOSINE AS A PLURISYSTEM MODULATOR IN SEPSIS AND THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS)

Beth A. Conlon, James D. Ross, and William R. Law

Department of Physiology and Biophysics, University of Illinois at Chicago, and Jesse Brown V.A. Medical Center, Chicago, IL 60612

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Background
3.1. Metabolic regulation of adenosine
3.2. Adenosine Receptors
3.3. Indirect Effects of Adenosine: Oxyradicals
4. Adenosine In Sepsis And SIRS
4.1. Regional Perfusion Affected by Adenosine in SIRS and Sepsis
4.1.1. Hepatosplanchnic circulation
4.1.2. Other Regional Perfusion changes attributable to adenosine.
4.1.3. Adenosine and Nitric Oxide (NO)
4.2. Cardiac Cytokine Expression
4.2.1. Direct and indirect effects of adenosine on cardiac TNF-alpha production
4.2.2. Transcriptional regulation of cardiac TNF-alpha by adenosine and reactive oxygen
4.3. Adenosine in Modulating Immune Function
4.3.1. Monocytes and Macrophages
4.3.2. Neutrophils
4.3.3. T-cells
5. Therapeutic Paradigms
5.1. Adenosine or Adenosine Precursors
5.2. Agonists and Antagonists
5.3. Manipulating Adenosine Metabolism
5.3.1. Adenosine Kinase
5.3.2. Adenosine Deaminase
6. Perspective
7. References

1. ABSTRACT

Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.