Pronounced Inflammatory Response to Endotoxaemia during Nighttime: A Randomised Cross-Over Trial

Mahdi Alamili,Jens Lykkesfeldt,Jacob Rosenberg,Klaus Bendtzen,Ismail Gögenur,Paul Proost

doi:10.1371/journal.pone.0087413

Mahdi Alamili, Jens Lykkesfeldt + Show 4 more

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https://doi.org/10.1371/journal.pone.0087413

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Abstract

BackgroundCircadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model.Design and MethodsA cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti-inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-R)-1 and -2, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, and IL-10 as well as YKL-40 and the oxidative stress markers malondialdehyde (MDA), ascorbic acid (AA) and dehydroascorbic acid (DHA) before and at 2, 4, 6 and 8 hours after LPS administration.ResultsThe levels of MDA and IL-10 where significantly higher during the day time (P<0.05) whereas levels of TNF-alpha, sTNF-RI, sTNF-RII, IL-1Ra, IL-6, and YKL-40 were higher (P<0.01 for all comparisons) during the night time. No significant differences were seen in the levels of AA and DHA.ConclusionA day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further.

Highlights

The existence of circadian variation in acute medical settings is well established [1,2,3]
Circadian variations exist in the circulating levels of lymphocytes, macrophages and neutrophils, and cytokines released from these cells [6,7], little is known about the circadian variations in the immunoinflammatory response accompanying septic conditions, where cytokines and oxidative stress play a crucial role [8,9,10,11]
Day-night difference in the inflammatory response Apart from IL-1beta, all pro- and anti-inflammatory cytokines, tumour-necrosis factor (TNF)-a, sTNF-RI and sTNF-RII, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10 increased significantly 2 and/or 4 hours after induction of endotoxaemia compared with baseline levels (Figures 1 and 2; and table 1)

Summary

Introduction

The existence of circadian variation in acute medical settings is well established [1,2,3]. The occurrence of acute myocardial infarction, sudden cardiac death, pulmonary thromboembolisms and stroke exhibits a distinct circadian variation [4]. In surgery, both major and minor abdominal surgery results in circadian disturbances [5] including a circadian distribution of postoperative cardiovascular events [4]. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model

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