title: 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.
authors.affiliation: Department of Anesthesiology, Klinikum Grosshadern, Munich, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Kaufmann
authors.forename: Alwin
authors.initials: A
authors.lastname: Hoelzl
authors.forename: Florian
authors.initials: F
authors.lastname: Schliephake
authors.forename: Theresia
authors.initials: T
authors.lastname: Hummel
authors.forename: Alexander
authors.initials: A
authors.lastname: Chouker
authors.forename: Lidia
authors.initials: L
authors.lastname: Łysenko
authors.forename: Klaus
authors.initials: K
authors.lastname: Peter
authors.forename: Manfred
authors.initials: M
authors.lastname: Thiel
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D058908:Adenosine A2 Receptor Agonists; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality
chemical_list: D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D006861:Hydrogen Peroxide; D000241:Adenosine