A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis.
BACKGROUND
Sepsis is currently treated with antibiotics and various adjunctive therapies that are not very effective.


METHODS
Mouse survival (4-5 days) and peritoneal and blood bacteria counts were determined after challenge with intraperitoneal lipopolysaccharide (LPS) or live Escherichia coli.


RESULTS
The A(2A) adenosine receptor (AR) agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e; 0.05-50 mu g/kg) protected mice from challenge with LPS, and protection occurred when treatment was delayed up to 24 h after challenge. Deletion of the A (2A) AR gene, Adora2a, inhibited protection by ATL146e. A putative A (3)AR agonist, N(6)-3-iodobenzyladenosine-5'-N-methyluronamide (IB-MECA; 500 mu g/kg but not 5 or 50 mu g/kg) protected mice from challenge with LPS. The protective effects of both ATL146e and IB-MECA were counteracted by the A(2A) AR selective antagonist 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)-phenol. In the live E. coli model, treatment with ATL146e (50 mu g/kg initiated 8 h after infection) increased survival in mice treated with ceftriaxone (5 days) from 40% to 100%. Treatment with ATL146e did not affect peritoneal numbers of live E. coli at the time of death or 120 h after infection but did increase numbers of peritoneal neutrophils and decreased the number of live E. coli in blood.


CONCLUSIONS
AR agonists increase mouse survival in endotoxemia and sepsis via A(2A) AR-mediated mechanisms and reduce the number of live bacteria in blood.
Sullivan
Gail W
GW
Department of Internal Medicine, University of Virginia, Charlottesville, Virginia, USA. gws3u@virginia.edu
Fang
Guodong
G
Linden
Joel
J
Scheld
W Michael
WM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011687:Purines / Q000494:pharmacology*; D043683:Receptors, Adenosine A2 / Q000276:immunology*; D018805:Sepsis / Q000276:immunology*; D016019:Survival Analysis
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D008070:Lipopolysaccharides; D011687:Purines; D043683:Receptors, Adenosine A2; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D000241:Adenosine