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Although the innate immune response protects the host from invading pathogens, an excessive response may also lead to collateral damage to normal tissues. Adenosine has been proposed as an immunomodulator capable of inhibiting inflammation and preventing tissue injury. The C34T nonsense mutation in the AMP deaminase 1 (AMPD1) gene is thought to increase the endogenous adenosine concentration and has been associated with improved prognosis and survival in ischemic heart disease. Caffeine on the other hand, acting as a nonselective adenosine receptor antagonist, could diminish adenosine-mediated effects. The present study evaluated the endotoxemia-induced adenosine response, subclinical renal damage and endothelium dysfunction in healthy male subjects. Furthermore, we investigated whether the LPS-induced inflammatory response is attenuated by AMPD1 and enhanced by Caffeine, as well as its effects on markers of endothelium activation (plasma ICAM, VCAM) and renal damage (urinary excretion of GSTA1-1 and GSTP1-1).
Thirty healthy male subjects received 2 ng/kg E. coli LPS. Three groups were evaluated in a double-blind randomized controlled setting; a LPS-placebo group (n = 10), LPS-placebo in AMPD1 subjects (n = 10), and a LPS-Caffeine group (4 mg/kg, n = 10).
During endotoxemia, the adenosine concentration increased from 10.0 ng/ml (9.0 to 15.3) at baseline to 15.5 ng/ml (13.0 to 22.3) 2 hours after LPS infusion (P = 0.003; Friedman). The response was similar between LPS groups. The increase in proinflammatory and anti-inflammatory cytokines (TNFα, IL-6, IL-10 and IL1RA) was similar in the three groups. Experimental endotoxemia resulted in endothelial dysfunction, measured by an increase in adhesion molecules and subclinical renal injury as measured by GSTA1- 1 and GSTP1-1. Inflammation induced subclinical end-organ damage was not influenced by either the AMPD1 SNP or treatment with Caffeine.
Human experimental endotoxemia induces an increase in circulating cytokine levels and subclinical endothelial and renal damage. Acute systemic inflammation is also associated with an increase in endogenous adenosine concentrations. Modulation of the adenosine metabolism through the presence of the AMPD1 and administration of Caffeine does not affect the innate immune response and its subsequent subclinical organ dysfunction.