title: [Adenosine reduces ischemia/reperfusion-induced liver injury by inhibiting leukocyte activation].
abstract: To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A2 receptor (A2R), we investigated the effects of adenosine and YT-146, selective A2A receptor (A2AR) agonist, on I/R-induced liver injury in rats. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil elastase release from isolated neutrophils by about 35% in vitro. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the endotoxin-stimulated TNF-alpha production by monocytes to less than 50% of the control. Although ZM241385, a selective A2AR antagonist, significantly enhanced the fMLP-induced neutrophil elastase release in isolated neutrophils in vitro, this agent did not affect the endotoxin-stimulated TNF-alpha production by monocytes. Male Wistar rats were subjected to complete ischemia of median and left lobes of liver for 60 min and the subsequent reperfusion. Serum levels of transaminases increased over time after hepatic I/R, peaking at 12 hrs after reperfusion. Intravenous infusion of Adenosine (1 and 10 mg/kg/hr) and YT-146 (0.1 and 1 mg/kg/hr) significantly inhibited the I/R-induced increases in serum transaminase levels 12 hrs after reperfusion. The I/R-induced decrease in hepatic tissue blood flow was significantly inhibited by adenosine and YT-146. Hepatic levels of TNF-alpha, cytokine-induced neutrophil chemoattractant (a member of interleukin-8), and myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by administration of adenosine and YT-146. However, ZM241385 did not reduce the I/R-induced liver injury and it inhibited neither the decrease in hepatic tissue blood flow, nor the indicators of leukocyte activation. These findings suggest that adenosine may reduce I/R-induced liver injury mainly by inhibiting hepatic TNF-alpha production via A2AR, thereby reducing neutrophil activation.
authors.affiliation: Department of Pharmacology, School of Medicine, Fukuoka University.
authors.forename: N
authors.initials: N
authors.lastname: Harada
authors.forename: K
authors.initials: K
authors.lastname: Okajima
authors.forename: T
authors.initials: T
authors.lastname: Katsuragi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D006801:Humans; D066298:In Vitro Techniques; D019272:Leukocyte Elastase / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D015427:Reperfusion Injury / Q000517:prevention & control*; D000637:Transaminases / Q000097:blood; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000480:Alkynes; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C097270:ZM 241385; D009240:N-Formylmethionine Leucyl-Phenylalanine; C070494:YT 146; D000637:Transaminases; D019272:Leukocyte Elastase; D000241:Adenosine