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J Infect Dis. 2004 May 15;189(10):1897-904. Epub 2004 Apr 28.

A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis.

Author information

1
Department of Internal Medicine, University of Virginia, Charlottesville, Virginia, USA. gws3u@virginia.edu

Abstract

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.

PMID:
15122527
DOI:
10.1086/386311
[Indexed for MEDLINE]

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