by Leijte, Guus P.;
Kiers, Dorien; van der Heijden, Wouter; Jansen, Aron; Gerretsen, Jelle;
Boerrigter, Verin; Netea, Mihai G.; Kox, Matthijs; Pickkers, Peter
Objective: To
investigate immunostimulatory effects of acetylsalicylic acid during
experimental human endotoxemia and in sepsis patients.
Design:
Double-blind, randomized, placebo-controlled study in healthy volunteers and ex
vivo stimulation experiments using monocytes of septic patients.
Setting:
Intensive care research unit of an university hospital.
Subjects: Thirty
healthy male volunteers and four sepsis patients. Interventions: Healthy
volunteers were challenged IV with endotoxin twice, at a 1-week interval, with
each challenge consisting of a bolus of 1 ng/kg followed by continuous
administration of 1 ng/kg/hr during 3 hours. Volunteers were randomized to
acetylsalicylic acid prophylaxis (80 mg acetylsalicylic acid daily for a 14-d
period, starting 7 d before the first endotoxin challenge), acetylsalicylic
acid treatment (80 mg acetylsalicylic acid daily for the 7-d period in-between
both endotoxin challenges), or the control group (receiving placebo).
Furthermore, monocytes of sepsis patients were incubated with acetylsalicylic
acid preexposed platelets and were subsequently stimulated with endotoxin.
Measurements and Main Results:
Acetylsalicylic acid prophylaxis enhanced plasma tumor necrosis factor-α
concentrations upon the first endotoxin challenge by 50% compared with the
control group (p = 0.02) but did not modulate cytokine responses during the
second endotoxin challenge. In contrast, acetylsalicylic acid treatment
resulted in enhanced plasma levels of tumor necrosis factor-α (+53%; p = 0.02),
interleukin-6 (+91%; p = 0.03), and interleukin-8 (+42%; p = 0.02) upon the
second challenge, whereas plasma levels of the key antiinflammatory cytokine
interleukin-10 were attenuated (–40%; p = 0.003). This proinflammatory
phenotype in the acetylsalicylic acid treatment group was accompanied by a
decrease in urinary prostaglandin E metabolite levels (–27% ± 7%; p = 0.01). Ex
vivo exposure of platelets to acetylsalicylic acid increased production of
tumor necrosis factor-α (+66%) and decreased production of interleukin-10
(–23%) by monocytes of sepsis patients. Conclusions:
Treatment, but not prophylaxis, with low-dose acetylsalicylic acid, partially
reverses endotoxin tolerance in humans in vivo by shifting response toward a
proinflammatory phenotype. This acetylsalicylic acid–induced proinflammatory
shift was also observed in septic monocytes, signifying that patients suffering
from sepsis-induced immunoparalysis might benefit from initiating
acetylsalicylic acid treatment.
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