七氟烷通过增强诱导型一氧化氮合酶在雄性小鼠中的表达促进巨噬细胞的杀菌特性
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Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice
背景与目的
具有抗炎特性的七氟烷在脓毒症动物模型中显示出较低死亡率。然而，在这种炎症情况下，其有益作用的潜在机制仍然不太了解。巨噬细胞在脓毒症的早期起着重要的作用，因为它们的任务是清除入侵的微生物，并通过释放促炎细胞来吸引其他免疫细胞。如白细胞介素-1β、白细胞介素-6、肿瘤坏死因子-α等.因此，作者假设七氟烷可以减轻巨噬细胞的促炎反应，同时保持其杀菌性。
方 法
在2%七氟烷存在和不存在的情况下，用脂多糖刺激小鼠骨髓巨噬细胞。检测细胞因子和诱导型一氧化氮合酶的表达及对荧光标记大肠杆菌(E.coli)的摄取。在体内毒素血症模型由氯胺酮和二甲苯嗪或4%七氟烷麻醉后腹腔注射脂多糖组成。观察到雄性小鼠(每组6只)共20小时。最后30 min腹腔注射荧光标记大肠杆菌。用流式细胞仪测定腹腔灌洗液和诱导型一氧化氮合酶表达以及腹腔巨噬细胞的大肠杆菌摄取。
结 果
体外实验表明，与对照组比较，七氟烷可使脂多糖诱导的诱导型一氧化氮合酶表达增加466%，巨噬细胞对荧光标记大肠杆菌的摄取率提高70%。抑制诱导型一氧化氮合酶的表达，在药理学上取消了这种增加的细菌摄取。与对照组相比，体内诱导型一氧化氮合酶表达增加669%，大肠杆菌吞噬功能提高49%。
结 论
在体内外七氟烷均通过诱导型一氧化氮合酶依赖性机制增强细菌的吞噬作用。因此，七氟醚增强内毒素血症中的杀菌和抗炎宿主防御机制。
原始文献摘要
Gerber TJ, Fehr VCO, Oliveira SDS, Hu G, Dull R, Bonini MG, Beck-Schimmer B,Minshall RD. Sevoflurane Promotes Bactericidal Properties of Macrophages through Enhanced Inducible Nitric Oxide Synthase Expression in Male Mice. Anesthesiology.2019 Oct 24. doi: 10.1097/ALN.0000000000002992. [Epub ahead of print] PubMed PMID: 31658116.
Background: Sevoflurane with its antiinflammatory properties has shown to decrease mortality in animal models of sepsis. However, the underlying mechanism of its beneficial effect in this inflammatory scenario remains poorly understood. Macrophages play an important role in the early stage of sepsis as they are tasked with eliminating invading microbes and also attracting other immune cells by the release of proinflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α. Thus, the authors hypothesized that sevoflurane mitigates the proinflammatory response of macrophages, while maintaining their bactericidal properties.
Methods: Murine bone marrow–derived macrophages were stimulated in vitro with lipopolysaccharide in the presence and absence of 2% sevoflurane. Expression of cytokines and inducible NO synthase as well as uptake of fluorescently labeled Escherichia coli (E. coli) were measured. The in vivo endotoxemia model consisted of an intraperitoneal lipopolysaccharide injection after anesthesia with either ketamine and xylazine or 4% sevoflurane. Male mice (n = 6 per group) were observed for a total of 20 h. During the last 30min fluorescently labeled E. coli were intraperitoneally injected. Peritoneal cells were extracted by peritoneal lavage and inducible NO synthase expression as well as E. coli uptake by peritoneal macrophages was determined using flow cytometry.
Results: In vitro, sevoflurane enhanced lipopolysaccharide-induced inducible NO synthase expression after 8 h by 466% and increased macrophage uptake of fluorescently labeled E. coli by 70% compared with vehicle-treated controls. Inhibiting inducible NO synthase expression pharmacologically abolished this increase in bacteria uptake. In vivo, inducible NO synthase expression was increased by 669% and phagocytosis of E. coli by 49% compared with the control group.
Conclusions: Sevoflurane enhances phagocytosis of bacteria by lipopolysaccharide-challenged macrophages in vitro and in vivo via an inducible NO synthase–dependent mechanism. Thus, sevoflurane potentiates bactericidal and antiinflammatory host-defense mechanisms in endotoxemia.
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贵州医科大学高鸿教授课题组
翻译：任文鑫 编辑：何幼芹 审校：王贵龙