Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study

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. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Leijte, Netea, Kox, and Pickkers designed the study. Drs. Leijte, Kiers, Jansen, and Boerrigter included the subjects, performed the experiments, and processed the samples. Drs. Leijte and van der Heijden performed the ex vivo experiments. Drs. van der Heijden and Gerretsen performed the laboratory analyses. Dr. Leijte performed the statistical analyses and drafted the article. Drs. Kiers, van der Heijden, Netea, Kox, and Pickkers critically revised the article and supervised the research. All authors read and approved the final article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://bit.ly/29S62lw). Dr. Netea was funded by a Spinoza grant of the Netherlands Organization for Scientific Research, and a Competitiveness Operational Program Grant of the Romanian Ministry of European Funds. The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Matthijs Kox, PhD, Department of Intensive Care Medicine, Radboud University Medical Center, internal mail 710, PO Box 9101, Nijmegen, The Netherlands. E-mail: matthijs.kox@radboudumc.nl Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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