Effects of Adenosine on Functions of Polymorphonuclear Leukocytes From Patients With Septic Shock

Abstract

Inasmuch as polymorphonuclear leukocytes (PMNs) play a major role in antibacterial defense but can also cause substantial tissue injury, drugs are needed which are able to attenuate tissue-toxic PMN reactions without inhibiting bactericidal mechanisms. Adenosine as a retaliatory metabolite is produced in response to metabolically unfavorable conditions like inflammation. However, it is not known whether adenosine can selectively downregulate adverse PMN reactions in sepsis. In this prospective clinical study, we characterized the effects of adenosine ex vivo on PMN functions in patients with septic shock ([SS] n = 33) and healthy volunteers ([HV] n = 33). The PMNs were primed by tumor necrosis factor-alpha (TNF-alpha) and subsequently stimulated with N-formyl methionyl-leucyl-phenylalanine (fMLP) to test for the formation of hydrogen peroxide (H2O2) in response to soluble inflammatory stimuli. The PMNs were also challenged by opsonized zymosan particles to assess adhesion, phagocytosis, and the associated H2O2 production. As compared with HV, PMNs from SS patients showed strongly enhanced tissue-toxic H2O2 production elicited by TNF-alpha/fMLP. Increasing concentrations of adenosine dose-dependently reduced this tissue-toxic H2O2 production in both groups with a half-maximal inhibitory concentration of 25 nmol/L and 114 nmol/L in HV and SS patients, respectively. This 4.6-fold decrease in the adenosine-mediated inhibition of PMNs from patients with septic shock was compensated by a 3-fold increase in the plasma concentrations of the nucleoside (HV, 42.5 +/- 2.9 nmol/L vs. SS, 125.6 +/- 18.2 nmol/L; mean +/- SEM). When the effects of adenosine were tested at a very high A2A receptor saturating concentration of 10 mol/L, neither adhesion, phagocytosis, nor the associated H2O2 production induced by opsonized zymosan was affected in both groups. These results were confirmed by the highly selective A2A agonist, CGS21680.Thus, adenosine or A2A agonists may be useful to selectively inhibit the potentially tissue-toxic H2O2 production elicited by soluble inflammatory mediators in patients with septic shock.

Adenosine A2A receptor modulates the oxidative stress response of primed polymorphonuclear leukocytes after parabolic flight

“…Using the model of PF, we determined dose-response curves by incubation of PMNs with increasing concentrations of adenosine. In agreement with previous reports [9], we demonstrated in healthy volunteers that adenosine is a sensitive inhibitor of potentially tissue-toxic PMN H 2 O 2 production elicited by the soluble stimuli TNF-␣ and fMLP. The dose-response curve observed before takeoff was of sigmoidal shape and values determined for half-maximal and maximum inhibition were well in the range of those reported for healthy PMNs by others [22].…”

“…In several in vitro and animal experimental studies, endogenously produced adenosine regulates the function of the innate and adaptive immune systems via targeting virtually every cell type involved in orchestrating the inflammatory response [9,16]. Adenosine controls a wide range of physiologic responses by binding to and activating 4 cell surface adenosine receptors, named A1, A2 A , A2 B , and A3 [17].…”

“…In the search for a regulatory mechanism that selectively limits this tissue-damaging capacity of PMNs without compromising their bactericidal effector mechanisms, it is interesting to note that the extent of reactive oxygen species released under certain conditions of leukocyte cell activation (e.g., sepsis) is limited by adenosine [9]. Adenosine is an endogenous purine nucleoside that is released from metabolically active cells and formed both intracellularly and extracellularly by degradation of adenosine triphosphate [10].…”

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

“…These receptors are classified in four types named A 1 , A 2A , A 2B , and A 3 -all of which are members of G protein-coupled family of receptors [5,7]. Indeed, of all known nucleosides, adenosine is the best characterized immunomodulator, showing anti-inflammatory effects [8] that are related to the inhibition of neutrophil migration and oxygen metabolite production [9][10][11]. Protective effects of adenosine and adenosine receptor agonists have also been shown in different models of inflammatory disease including asthma [12], inflammatory bowel disease [13], endotoxin-mediated shock [14], rheumatoid arthritis [15], sepsis [16], and wound healing [17].…”

Adenosine A2A-Receptor Stimulation Inhibits Lipopolysaccharide-Induced Interleukin-18 Production in Monocytes

“…In animal models, A2AR agonists can prevent death from LPS or sepsis (8). Adenosine or A 2 A agonists are reported to inhibit the potentially tissue-toxic H 2 O 2 production elicited by soluble inflammatory mediators in patients with septic shock (9). On the other hand, it is reported that A2AR knockout mice are protected from the lethal effect of sepsis and exhibit improved bacterial clearance compared with wild-type animals (10).…”