Intensive Care Unit, Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China.
Mol Med Rep. 2022 Jan;25(1). doi: 10.3892/mmr.2021.12541. Epub 2021 Nov 23.
Simvastatin exerts a protective effect during sepsis (SP) in animal models; however, the underlying mechanism is not completely understood, particularly in human SP. Neutrophils are a critical effector in the host inflammatory response to SP. Therefore, the present study aimed to investigate the effect of simvastatin on neutrophils in human SP. Neutrophils were isolated from the peripheral venous blood of adult patients with SP and healthy volunteers (HP). Cell viability was analyzed using the MTT assay. Intracellular reactive oxygen species (ROS) generation and the concentrations of inflammatory mediators were also assessed using flow cytometry and ELISA. The results demonstrated that the cell viability of neutrophils from the SP group was significantly decreased compared with that in the HP group, and that treatment with simvastatin partly reversed the reduced cell viability. Furthermore, simvastatin administration significantly decreased ROS production and the concentrations of TNF‑α and IL‑6, which were significantly increased in neutrophils isolated from the SP group. Simvastatin also enhanced autophagy induction, as indicated by the promotion of the conversion of LC3I to LC3II and the increased expression levels of Beclin 1 in SP neutrophils. Treatment with 3‑methyladenine, an autophagy inhibitor, completely blocked the protective effects of simvastatin on neutrophils from SP, including the effects of simvastatin on the inhibition of inflammation, oxidative stress and improving cell viability. Collectively, the present study provided evidence for the simvastatin‑induced autophagic process of neutrophils involved in human SP, which protects neutrophils and partially attenuates the inflammatory response and oxidative stress. Therefore, the augmentation of neutrophil autophagy may serve as a potential therapeutic target for patients with SP.
辛伐他汀在动物模型的脓毒症（SP）中发挥保护作用；然而，其潜在机制尚不完全清楚，尤其是在人类 SP 中。中性粒细胞是宿主对 SP 炎症反应的关键效应细胞。因此，本研究旨在探讨辛伐他汀对人类 SP 中性粒细胞的影响。从成人 SP 患者和健康志愿者（HP）的外周静脉血中分离中性粒细胞。使用 MTT 测定法分析细胞活力。还通过流式细胞术和 ELISA 评估细胞内活性氧物种（ROS）的产生和炎症介质的浓度。结果表明，SP 组中性粒细胞的细胞活力明显低于 HP 组，而辛伐他汀处理部分逆转了降低的细胞活力。此外，辛伐他汀给药可显著降低 ROS 产生以及 TNF-α和 IL-6 的浓度，SP 组分离的中性粒细胞中这些物质的浓度显著增加。辛伐他汀还增强了自噬诱导，如 LC3I 向 LC3II 的转化和 SP 中性粒细胞中 Beclin 1 表达水平的增加所表明的。自噬抑制剂 3-甲基腺嘌呤的处理完全阻断了辛伐他汀对 SP 中性粒细胞的保护作用，包括辛伐他汀对炎症、氧化应激和提高细胞活力的抑制作用。总之，本研究为涉及人类 SP 的中性粒细胞中辛伐他汀诱导的自噬过程提供了证据，该过程保护中性粒细胞并部分减轻炎症反应和氧化应激。因此，中性粒细胞自噬的增强可能成为 SP 患者的潜在治疗靶点。
