Department of Emergency Medicine, CHA University School of Medicine, Seongnam 13497, Gyeonggi, Korea.
Department of Emergency Medicine, CHA Bundang Medical Center, CHA University, Seongnam 13497, Gyeonggi, Korea.
Int J Mol Sci. 2022 Jun 13;23(12):6581. doi: 10.3390/ijms23126581.
Immune suppression is known to occur during sepsis. Endotoxin tolerance is considered a mechanism of immune suppression in sepsis. However, the timing and serial changes in endotoxin tolerance have not been fully investigated. In this study, we investigated serial changes in endotoxin tolerance in a polymicrobial sepsis model. Herein, we used a rat model of fecal slurry polymicrobial sepsis. After induction of sepsis, endotoxin tolerance of peripheral blood mononuclear cells (PBMCs) and splenocytes was measured at various time points (6 h, 12 h, 24 h, 48 h, 72 h, 5 days, and 7 days), through the measurement of TNF-α production after stimulation with lipopolysaccharide (LPS) in an ex vivo model. At each time point, we checked for plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 levels. Moreover, we analyzed reactive oxygen species (ROS) as measured by 2',7'-dichlorodihydrofluorescein, plasma lactate, serum alanine aminotransferase (ALT), and creatinine levels. Nuclear factor (NF)-κB, IL-1 receptor-associated kinase (IRAK)-M, and cleaved caspase 3 levels were measured in the spleen. Endotoxin tolerance, measured by TNF-α production stimulated through LPS in PBMCs and splenocytes, was induced early in the sepsis model, starting from 6 h after sepsis. It reached a nadir at 24 to 48 h after sepsis, and then started to recover. Endotoxin tolerance was more prominent in the severe sepsis model. Plasma cytokines peaked at time points ranging from 6 to 12 h after sepsis. ROS levels peaked at 12 h and then decreased. Lactate, ALT, and serum creatinine levels increased up to 24 to 48 h, and then decreased. Phosphorylated p65 and IRAK-M levels of spleen increased up to 12 to 24 h and then decreased. Apoptosis was prominent 48 h after sepsis, and then recovered. In the rat model of polymicrobial sepsis, endotoxin tolerance occurred earlier and started to recover from 24 to 48 h after sepsis.
免疫抑制已知发生于脓毒症期间。内毒素耐受被认为是脓毒症中免疫抑制的一种机制。然而，内毒素耐受的时间和连续变化尚未得到充分研究。在这项研究中，我们研究了多微生物脓毒症模型中内毒素耐受的连续变化。在此，我们使用大鼠粪便多微生物脓毒症模型。在诱导脓毒症后，通过在体外模型中用脂多糖（LPS）刺激测量外周血单核细胞（PBMC）和脾细胞的内毒素耐受，在不同时间点（6 h、12 h、24 h、48 h、72 h、5 天和 7 天）测量 TNF-α 的产生。在每个时间点，我们检查了血浆肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6 和 IL-10 水平。此外，我们分析了通过 2'，7'-二氯二氢荧光素测量的活性氧（ROS）、血浆乳酸、血清丙氨酸氨基转移酶（ALT）和肌酐水平。脾中测量核因子（NF）-κB、IL-1 受体相关激酶（IRAK）-M 和切割的半胱天冬酶 3 水平。通过 LPS 刺激 PBMC 和脾细胞测量的内毒素耐受在脓毒症模型中早期诱导，从脓毒症后 6 h 开始。它在脓毒症后 24 至 48 h 达到最低点，然后开始恢复。内毒素耐受在严重脓毒症模型中更为突出。血浆细胞因子在脓毒症后 6 至 12 h 之间的时间点达到峰值。ROS 水平在 12 h 达到峰值，然后下降。乳酸、ALT 和血清肌酐水平增加至 24 至 48 h，然后下降。脾中磷酸化 p65 和 IRAK-M 水平在 12 至 24 h 之间增加，然后下降。脓毒症后 48 h 出现明显的细胞凋亡，然后恢复。在大鼠多微生物脓毒症模型中，内毒素耐受发生得更早，从脓毒症后 24 至 48 h 开始恢复。
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