title: A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis.
abstract: 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. A(1) adenosine receptor (A(1)AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A(1)AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A(1)AR knockout mice (A(1) knockout) and their wild-type (A(1) wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A(1) knockout mice or A(1) wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A(1)AR antagonist) had a significantly higher mortality rate compared with A(1) wild-type mice following CLP. Mice lacking endogenous A(1)ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-alpha 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A(1) knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A(1) wild-type littermate controls. No difference in renal tubular apoptosis was detected between A(1) knockout and A(1) wild-type mice. We conclude that endogenous A(1)AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
authors.affiliation: Department of Anesthesiology, Columbia University, New York, NY 10032-3784, USA.
authors.forename: George
authors.initials: G
authors.lastname: Gallos
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Ruyle
authors.forename: Charles W
authors.initials: CW
authors.lastname: Emala
authors.forename: H Thomas
authors.initials: HT
authors.lastname: Lee
mesh_terms: D000818:Animals; D015415:Biomarkers; D002432:Cecum / Q000293:injuries / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D007249:Inflammation / Q000378:metabolism; D007674:Kidney Diseases / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D007677:Kidney Function Tests; D008026:Ligation; D008107:Liver Diseases / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008111:Liver Function Tests; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010538:Peritonitis / Q000401:mortality / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000502:physiology*; D018805:Sepsis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016328:NF-kappa B; D043682:Receptor, Adenosine A1; D009195:Peroxidase