title: Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass.
abstract: Granulocyte adhesion to ischemic tissue, mediated in large part by beta 2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this agent might modulate up-regulation of this adhesion receptor. In vitro, whole blood was incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucyl-phenylalanine, and granulocyte CD11b measured. Acadesine significantly (p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation (p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low- and high-dose treatment groups, there was significant (p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte CD11b in vitro, and acadesine is capable of a similar inhibition during in vivo cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury.
authors.affiliation: Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520-8035.
authors.forename: J P
authors.initials: JP
authors.lastname: Mathew
authors.forename: C S
authors.initials: CS
authors.lastname: Rinder
authors.forename: J B
authors.initials: JB
authors.lastname: Tracey
authors.forename: L A
authors.initials: LA
authors.lastname: Auszura
authors.forename: T
authors.initials: T
authors.lastname: O'Connor
authors.forename: E
authors.initials: E
authors.lastname: Davis
authors.forename: B R
authors.initials: BR
authors.lastname: Smith
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D018821:CD18 Antigens; D002315:Cardiopulmonary Bypass; D005260:Female; D006801:Humans; D016177:Macrophage-1 Antigen; D008297:Male; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016024:Receptors, Cytoadhesin / Q000187:drug effects / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018821:CD18 Antigens; D016177:Macrophage-1 Antigen; D016024:Receptors, Cytoadhesin; D012263:Ribonucleosides; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000241:Adenosine