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.

A1adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

“…In animal models, potentiating adenosine effects (by either administration of adenosine receptor agonists or inhibiting reuptake mechanisms) have been shown to improve outcomes in sepsis (1,12,34,37). The A 2a AR is known to have anti-inflammatory effects and therefore has been an adenosine receptor subtype evaluated for its potential role in sepsis.…”

The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A2Aand A3Receptors

“…On the other hand, a close correlation has been found between the severity of inflammation and a local increase in both expression and activity of adenosine deaminase, the enzyme responsible for conversion of endogenous adenosine into inosine, which leads to a decreased availability of biologically active adenosine (Conlon and Law, 2004;Desrosiers et al, 2007). Based on this knowledge, the pharmacological inhibition of adenosine deaminase is regarded as a novel therapeutic approach to counteract inflammation in several pathological conditions (Adanin et al, 2002;Law et al, 2003;Kayhan et al, 2008). In line with this concept, we previously provided evidence on the protective effects exerted by drugs acting as adenosine deaminase inhibitors against the onset of experimental colitis.…”

Anti-inflammatory effect of a novel locally acting A2A receptor agonist in a rat model of oxazolone-induced colitis

“…When considering the effects of PSB-0777 on body weight, microscopic damage score, and tissue TNF and MPO levels, as an index of inflammatory cell infiltrate, we observed an amelioration of all these inflammatory parameters. In particular, animals treated with PSB-0777 displayed a significant increase in body weight gain as well as an improvement of the histological damage score and a decrease in TNF and MPO levels, thus providing additional evidence that the pharmacological stimulation of A 2A receptors at inflammatory sites can result in a significant attenuation of the phlogistic processes [15,35,36]. The increase in body weight resulted very likely from the local action of PSB-0777 in the intestine, since the systemic administration of PSB-0777 was previously found to lead to a decrease in body weight in mice fed with high-fat diet due to the activation of A 2A adenosine receptors in adipocytes [37].…”