Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis.
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.
Adanin
Simon
S
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago, Illinois 60612, USA.
Yalovetskiy
Igor V
IV
Nardulli
Beth A
BA
Sam
Albert D
AD
Jonjev
Zivojin S
ZS
Law
William R
WR
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
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