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ivojin
S.
Jonjev1, andDepartments of 1 Physiology and Biophysics and 2 Surgery, University of Illinois College of Medicine, Chicago, Illinois 60612
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)-
,
interleukin (IL)-1
, and IL-10 were measured in serum and in liver
and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum
TNF-, IL-1, and IL-10. PNT dose dependently attenuated, without
ablating, the elevation in serum TNF- and IL-1 and raised liver
and spleen IL-10. PNT also attenuated elevation of TNF- 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.
shock; cytokines; oxyradical
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