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Am J Physiol Renal Physiol (March 22, 2005). doi:10.1152/ajprenal.00470.2004
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Submitted on December 29, 2004
Accepted on March 22, 2005

A1 Adenosine Receptor Knock-out Mice Exhibit Increased Mortality, Renal Dysfunction and Hepatic Injury in Murine Septic Peritonitis

George Gallos1, Thomas D. Ruyle1, Charles W. Emala1, and H. Thomas Lee1*

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

* To whom correspondence should be addressed. E-mail: tl128{at}columbia.edu.

Sepsis is a leading cause of multi-organ 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 20G needle. A1 knockout mice or A1 wild type mice treated with 1,3-dipropyl-8- cyclopentylxanthine (DPCPX, a selective A1AR antagonist) had a significantly higher mortality rate compared to 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-{alpha}, 24 hours after induction of sepsis compared to wild type mice. Renal cortico-medullary junction from A1 knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding pro-inflammatory cytokines compared to 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.




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