[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
FIGURES
Figure 1. Metabolism of Adenosine: Intracellular. Partial schema of enzyme pathways pertinent to the regulation of intracellular adenosine concentrations. Adenosine monophosphate (AMP) can be directly deaminated to inosine monophosphate (IMP) by AMP deaminase, or acted upon by an endo-5'-nucleotidase to form adenosine. Adenosine can be rephosphorylated to AMP by adenosine kinase, or deaminated to inosine by adenosine deaminase. IMP can also be a source of inosine by the same endo-5'-nucleotidase. Hypoxanthine is formed after removal of ribose from inosine by the actions of purine nucleoside phosphorylase. Hypoxanthine can be salvaged to IMP by hypoxanthine phosphoribosyltransferase, or enter the xanthine oxidase pathway to form xanthine and uric acid sequentially, with the generation of oxyradicals as a byproduct. Intracellular adenosine can be transported into and out of the cell by membrane-associated transporter proteins.
Figure 2. Metabolism of Adenosine: Extracellular. Partial schema of enzyme pathways pertinent to the regulation of extracellular adenosine concentrations. Cyclic adenosine monophosphate (cAMP) can be transported out of cells upon activation of adenylyl cyclase. The actions of an ecto-phosphodiesterase on cAMP results in the formation of AMP. AMP can also be directly released by some cell types. AMP is acted upon by an ecto-5'-nucleotidase to form adenosine. Adenosine can then be transported into the cell, or deaminated to inosine by adenosine deaminase. Hypoxanthine is formed after removal of ribose from inosine by the actions of purine nucleoside phosphorylase. Hypoxanthine enters the xanthine oxidase pathway to form xanthine and uric acid sequentially, with the generation of oxyradicals as a byproduct.
Figure 3.Cardiac Adenosine Deaminase Activity in SIRS. Adenosine deaminase activity is elevated in rat hearts during SIRS associated with peritonitis. Diffuse peritonitis with fluid resuscitation was induced by peritoneal introduction of a slurry of cecal material (400 mg/kg in D5W) as previously described (30;104). Hearts were obtained at 1, 3, and 6 days after the septic insult, and adenosine deaminase (ADA) measured in whole heart homogenates according to previously described methods (70).
Figure 4. Adenosine is a Plurisystem Modulator. Adenosine is a plurisystem mediator/modulator, influencing responses in various cell and tissue types, and via numerous receptor and cell signaling pathways. This figure presents a partial summary of interrelated system effects of adenosine that exemplify the potential roles during conditions associated with systemic inflammatory response syndrome (SIRS). Adenosine can be generated by intracellular and extracellular enzyme pathways depending upon the specific and unique conditions giving rise to elevated extracellular concentrations. Both equilibrative and concentrative adenosine transport proteins can move adenosine across cellular membranes, influencing extracellular adenosine concentrations. the enzymes involved in adenosine metabolism in and out of the cell are covered in Figures 1&2. LPS and other inflammatory stimuli activate innate immune cells, including macrophages and neutrophils. Paracrine and autocrine communication through cytokines can lead to an exaggerated inflammatory response that moves beyond the confines of the locale wherein the inflammatory stimulus originated. By direct actions on innate immune cells, and interruption intracellular signaling molecules, the inflammatory process is generally abated, but not ablated by adenosine. In the regions where it is produced in sufficient quantities, adenosine can also cause regional vasodilation by direct actions on smooth muscle, of by influencing NO synthase. The latter is influenced both by adenosine stimulation of NOS activity, and altering expression of the iNOS protein.