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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-
, 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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