Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study
Treatment With Acetylsalicylic Acid Reverses Endotoxin Tolerance in Humans In Vivo: A Randomized Placebo-Controlled Study
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DOI：
10.1097/ccm.0000000000003630
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发表时间：
2019-04-01
影响因子：
8.8
通讯作者：
Pickkers, Peter
中科院分区：
文献类型：
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作者：
Leijte, Guus P.;Kiers, Dorien;Pickkers, Peter
目的：探讨乙酰水杨酸在实验性人体内毒素血症和脓毒症患者中的免疫刺激作用。设计：健康志愿者双盲、随机、安慰剂对照研究和败血症患者单核细胞体外刺激实验。地点：一所大学医院重症监护研究室。研究对象：30名健康男性志愿者和4名脓毒症患者。干预：健康志愿者静脉注射内毒素2次，间隔1周，每次挑战包括静脉推注1 ng/kg，然后连续注射1 ng/kg/h，持续3小时。志愿者被随机分为乙酰水杨酸预防组(每天80 mg乙酰水杨酸，持续14天，从第一次内毒素攻击前7天开始)，乙酰水杨酸治疗(在两次内毒素攻击之间的7天期间，每天80 mg乙酰水杨酸)，或对照组(接受安慰剂)。此外，脓毒症患者的单核细胞与乙酰水杨酸预先暴露的血小板孵育，然后用内毒素刺激。测量和主要结果：乙酰水杨酸预防使第一次内毒素攻击时血浆肿瘤坏死因子-a浓度比对照组增加50%(p=0.02)，但在第二次内毒素攻击时不调节细胞因子反应。相反，乙酰水杨酸治疗导致血浆肿瘤坏死因子-a(+53%；p=0.02)、白介素6(+91%；p=0.03)和白介素8(+42%；p=0.02)水平升高，而关键抗炎细胞因子白介素10水平降低(-40%；p=0.003)。乙酰水杨酸治疗组的这种促炎表型伴随着尿前列腺素E代谢物水平的下降(-27%+/-7%；p=0.01)。体外暴露于乙酰水杨酸可增加脓毒症患者单核细胞产生肿瘤坏死因子-α(+66%)，减少产生白介素10(-23%)。结论：小剂量乙酰水杨酸治疗而不是预防，通过将反应转变为促炎表型，在体内部分逆转了人类的内毒素耐受。在脓毒症单核细胞中也观察到了这种乙酰水杨酸诱导的致炎转变，这意味着患有脓毒症诱导的免疫麻痹的患者可能受益于开始乙酰水杨酸治疗。
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-a 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-a (+ 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-a (+ 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.