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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/F369    most recent 00470.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Gallos, G. Articles by Lee, H. T. Search for Related Content PubMed PubMed Citation Articles by Gallos, G. Articles by Lee, H. T.

A₁ adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York

Submitted 29 December 2004 ; accepted in final form 22 March 2005

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A₁ adenosine receptor (A₁AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A₁AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A₁AR knockout mice (A₁ knockout) and their wild-type (A₁ wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A₁ knockout mice or A₁ wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A₁AR antagonist) had a significantly higher mortality rate compared with A₁ wild-type mice following CLP. Mice lacking endogenous A₁ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor- 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A₁ knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A₁ wild-type littermate controls. No difference in renal tubular apoptosis was detected between A₁ knockout and A₁ wild-type mice. We conclude that endogenous A₁AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.

acute renal failure; multiorgan injury; survival

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