title: Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis.
abstract: By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
authors.affiliation: Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Adanin
authors.forename: Igor V
authors.initials: IV
authors.lastname: Yalovetskiy
authors.forename: Beth A
authors.initials: BA
authors.lastname: Nardulli
authors.forename: Albert D
authors.initials: AD
authors.lastname: Sam
authors.forename: Zivojin S
authors.initials: ZS
authors.lastname: Jonjev
authors.forename: William R
authors.initials: WR
authors.lastname: Law
mesh_terms: D000243:Adenosine Deaminase / Q000502:physiology*; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001424:Bacterial Infections / Q000378:metabolism*; D001769:Blood / Q000378:metabolism; D002908:Chronic Disease; D019446:Endotoxemia / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D015649:Pentostatin / Q000494:pharmacology; D010545:Peroxides / Q000378:metabolism; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D010545:Peroxides; D058915:Purinergic P1 Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015649:Pentostatin; C031433:8-(4-sulfophenyl)theophylline; D013806:Theophylline; D000243:Adenosine Deaminase