Institute of Medical Psychology and Behavioral Immunobiology, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Department of Nephrology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Neuroimmunomodulation. 2023;30(1):268-276. doi: 10.1159/000534444. Epub 2023 Oct 5.
Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 and 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, the two key features of inflammation-associated depression.
Healthy male volunteers (N = 18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms.
Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during the acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment.
Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent lipopolysaccharide-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.
实验性内毒素血症是一种全身性炎症的转化模型，它极大地促进了我们对疾病行为和炎症相关抑郁的理解。以前使用该模型的研究表明，在炎症的急性期，细胞因子水平、内分泌变化和心理疾病症状之间存在很强的关联。本随机、双盲、安慰剂对照交叉研究的目的是深入了解内毒素给药后的潜在急性后生理和心理后果，这些后果可能在注射后 24 至 72 小时之间持续存在或新出现。主要重点是血清 C 反应蛋白 (CRP) 水平与情感症状之间的关联，以及昼夜皮质醇谱的变化，这是炎症相关抑郁的两个关键特征。
健康男性志愿者（N=18）在相隔 7 天的 2 天内分别接受内毒素（0.8ng/kg）或安慰剂注射。在注射后的急性和后期阶段采集血液和唾液样本，以测量血液炎症标志物（白细胞介素[IL]-6、IL-1 受体拮抗剂[ra]、CRP）和唾液皮质醇水平。此外，参与者完成了一套全面的问卷，以评估身体和心理疾病症状。
内毒素处理诱导了血浆 IL-6 的短暂升高和更长时间的 IL-1ra 升高。血清 CRP 的增加与细胞因子相比延迟，在 24 小时达到峰值，并在注射后 72 小时逐渐减少。炎症反应伴随着身体和心理疾病症状，这些症状仅在急性期出现，而在后期阶段没有任何症状持续或复发。唾液皮质醇水平在急性期显著升高，并表现出明显的昼夜变化。然而，在治疗后的日子里，皮质醇昼夜模式在安慰剂和内毒素条件之间没有观察到显著差异。
我们的研究结果表明，在炎症相关抑郁患者中升高的 CRP 似乎与抑郁症状无关。此外，单次炎症发作不足以改变炎症相关抑郁中观察到的昼夜皮质醇模式。此外，在急性期之外，持续的内毒素诱导的心理和生理变化的缺失进一步支持了内毒素在人类中的安全性。
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