Published in:
Open Access
01-12-2008 | Research article
An A2Aadenosine receptor agonist, ATL313, reduces inflammation and improves survival in murine sepsis models
Authors:
Christopher C Moore, Edward N Martin, Grace H Lee, Tom Obrig, Joel Linden, W Michael Scheld
Published in:
BMC Infectious Diseases
|
Issue 1/2008
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Abstract
Background
The pathophysiology of sepsis is due in part to early systemic inflammation. Here we describe molecular and cellular responses, as well as survival, in A2A adenosine receptor (AR) agonist treated and untreated animals during experimental sepsis.
Methods
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.
Results
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).
Conclusion
Further studies are warranted to determine the clinical utility of ATL313 as a novel treatment for sepsis.