Guo Feng, Ding Ying, Yu Xue, Cai Xiujun
Department of Intensive Care Unit, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
Department of Intensive Care Unit, Sir Run Run Shaw Hospital Xiasha Campus, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, P.R. China.
Exp Ther Med. 2018 Jun;15(6):5487-5494. doi: 10.3892/etm.2018.6094. Epub 2018 Apr 24.
Dexmedetomidine, midazolam and propofol are common sedative drugs used in the intensive care unit. Lipopolysaccharides (LPS) are a potent inducer of human dendritic cells (DCs) maturation and survival, which induces cytokine production. The present study aimed to investigate the effect and mechanisms of sedative drugs on LPS-induced cytokine production in DCs. The mouse bone marrow-derived dendritic DC2.4 cell line was used in the present study. The Cell Counting Kit-8 assay was used to measure the viability of cells. Tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 mRNA expression levels and contents were measured using reverse transcription-quantitative polymerase chain reaction and ELISA, respectively. The expression levels of proteins associated with nuclear factor-κB (NF-κB) and mitogen activated protein kinase signaling pathways were assessed by western blotting. The three sedatives had different roles on TNF-α, IL-1β, IL-6, and IL-10 mRNA expression levels and content in DCs. Dexmedetomidine promoted inflammatory cytokine production at high clinical concentrations (10, 1 and 0.1 µM), however suppressed them at the lowest clinical concentration (0.001 µM), which was associated with NF-κB and c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) signaling. Midazolam inhibited inflammatory cytokine production via suppression of the NF-κB and JNK signaling pathways. Propofol partly inhibited inflammatory cytokine production, including IL-1β and IL-6, and the anti-inflammatory effect may result from inhibition of JNK-MAPK, and enhanced NF-κB and extracellular signal-regulated kinase-MAPK signaling at clinical concentrations. The present study helped to elucidate the function of sedatives in LPS-induced cytokine production in DCs, which will facilitate rational implementation of these sedatives in patients undergoing tracheal intubation with sepsis or multiple organ dysfunction syndrome.
右美托咪定、咪达唑仑和丙泊酚是重症监护病房常用的镇静药物。脂多糖（LPS）是人类树突状细胞（DCs）成熟和存活的强效诱导剂，可诱导细胞因子产生。本研究旨在探讨镇静药物对LPS诱导的DCs细胞因子产生的影响及其机制。本研究使用了小鼠骨髓来源的树突状DC2.4细胞系。采用细胞计数试剂盒-8法检测细胞活力。分别使用逆转录-定量聚合酶链反应和酶联免疫吸附测定法检测肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-6和IL-10的mRNA表达水平及含量。通过蛋白质印迹法评估与核因子-κB（NF-κB）和丝裂原活化蛋白激酶信号通路相关的蛋白质表达水平。这三种镇静剂对DCs中TNF-α、IL-1β、IL-6和IL-10的mRNA表达水平及含量具有不同作用。右美托咪定在高临床浓度（10、1和0.1µM）时促进炎性细胞因子产生，但在最低临床浓度（0.001µM）时抑制它们，这与NF-κB和c-Jun氨基末端激酶（JNK）-丝裂原活化蛋白激酶（MAPK）信号通路有关。咪达唑仑通过抑制NF-κB和JNK信号通路抑制炎性细胞因子产生。丙泊酚部分抑制炎性细胞因子产生，包括IL-1β和IL-6，其抗炎作用可能源于对JNK-MAPK的抑制，以及在临床浓度下增强的NF-κB和细胞外信号调节激酶-MAPK信号通路。本研究有助于阐明镇静剂在LPS诱导的DCs细胞因子产生中的作用，这将有助于在患有脓毒症或多器官功能障碍综合征的气管插管患者中合理使用这些镇静剂。
