An A2A adenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models

Sepsis was induced in mice by intraperitoneal inoculation of live bacteria (Escherichia coli or Staphylococcus aureus) or lipopolysaccharide (LPS). Mice inoculated with live bacteria were treated with an A2A AR agonist (ATL313) or phosphate buffered saline (PBS), with or without the addition of a dose of ceftriaxone. LPS inoculated mice were treated with ATL313 or PBS. Serum cytokines and chemokines were measured sequentially at 1, 2, 4, 8, and 24 hours after LPS was administered. In survival studies, mice were followed until death or for 7 days.There was a significant survival benefit in mice infected with live E. coli (100% vs. 20%, p = 0.013) or S. aureus (60% vs. 20%, p = 0.02) when treated with ATL313 in conjunction with an antibiotic versus antibiotic alone. ATL313 also improved survival from endotoxic shock when compared to PBS treatment (90% vs. 40%, p = 0.005). The serum concentrations of TNF-α, MIP-1α, MCP-1, IFN-γ, and IL-17 were decreased by ATL313 after LPS injection (p < 0.05). Additionally, ATL313 increased the concentration of IL-10 under the same conditions (p < 0.05). Circulating white blood cell concentrations were higher in ATL313 treated animals (p < 0.01).Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.Approximately 900,000 cases of sepsis occur annually in the United States, causing roughly 210,000 deaths and costing almost 17 billion dollars [1]. The overwhelming inflammation that occurs along with infection during sepsis has been the target of several therapeutic interventions [2]. Unfortunately, despite successful treatment in animal models, antibody neutralization of individual components of this inflammation has not proved beneficial for the majority of patients in clinical sepsis trials [3].Tissue hypoxia, as occurs in sepsis, enhances breakdown of adenosine triphosphate (ATP) to adenosine monophosphate (AMP), which is then dephosphorylated by the cytosolic 5'nucloeotidase to aden