辛伐他汀对脓毒症和严重脓毒症患者外周血单核细胞Toll样受体4的影响

Influence of simvastatin treatment on Toll-like receptor 4 in monocytes of peripheral blood in patients with sepsis and severe sepsis

目的观察辛伐他汀对脓毒症和严重脓毒症患者外周血单核细胞Toll样受体4（TLR4）表达的影响及意义。方法采用前瞻性随机对照试验，以2013年8月至2015年6月河南省人民医院重症医学科收治的106例脓毒症患者和92例严重脓毒症患者为研究对象，两组人群均按随机数字表法分为常规治疗组和辛伐他汀治疗组。所有患者均参照2012年国际脓毒症指南治疗，脓毒症患者辅以抗感染、营养支持和对症治疗等措施，严重脓毒症患者同时给予早期目标导向治疗（EGDT）；辛伐他汀组患者每日口服或经胃肠营养饲管加用辛伐他汀40mg，至少持续15d。在入重症加强治疗病房（ICU）1、5、10、15d取外周血分离单核细胞，采用流式细胞仪检测TLR4／CD14＋双阳性单核细胞表面TLR4的表达，并观察治疗期间不良反应发生情况。结果无论在脓毒症还是严重脓毒症患者中，辛伐他汀组（分别为59例和54例）外周血TLR4表达水平均随治疗时间延长呈下降趋势。在脓毒症患者中，辛伐他汀组TLR4水平于入ICU10d起即与常规治疗组（47例）出现了统计学差异，并持续至15d[平均荧光强度（MFI）：10d为21（19，28）比27（25：33），Z=2．198，P=O．021；15d为16（15，21）比26（23，34），Z=4．611，P=O．002]；而在严重脓毒症患者中，辛伐他汀组各时间点TLR4水平与常规治疗组（38例）比较差异均无统计学意义[MFI：1d为55（52，63）比56（48，65），Z=0．313，P=0．692；5d为47（42，56）比49（41，58），Z=0．827，P=0．533；10d为40（35，42）比42（37，45），Z=1．012，P=0．301；15d为33（30，38）比38（35，41），Z=0．539，P=0．571]。治疗过程中两组人群均未发现有关辛伐他汀的不良反应事件发生。结论他汀类药物可显著降低脓毒症患者外周血单核细胞表面TLR4表达水平，而对严重脓毒症患者的TLR4表达水平无显著影响。他汀类药物在两组人群中对TLR4介导的炎症反应的抑制作用不同，可能是其疗效不同的原因之一。

Objective To investigate the influence of simvastatin treatment on Toll-like receptor 4 （TLR4） in monocytes of peripheral blood in patients with sepsis and severe sepsis and its significance. Methods A prospective randomized controlled trial was conducted. 106 patients with sepsis and 92 patients with severe sepsis admitted to Department of Critical Care Medicine of Henan Provincial People＇s Hospital from August 2013 to June 2015 were enrolled. These two groups of patients were randomized into conventional treatment group and simvastatin group. All patients received treatment according to the 2012 International Sepsis Treatment Guidelines, including anti-infection drugs, nutritional support, and palliative treatment, and the patients with severe sepsis were given early goal-directed therapy （EGDT）. The patients in simvastatin group received simvastatin 40 mg daily orally for at least 15 days. The peripheral blood was collected and the monocytes were isolated at 1, 5, 10, 15 days after intensive care unit （ICU） admission. TLR4 expression on the surface of TLR4/CD 14＋ double positive monocytes was determined by flow cytometry, and adverse reaction was observed during treatment. Results TLR4 expression on the surface of monocytes showed a tendency of decreasing with prolongation of simvastatin treatment in the simvastatin group in patients with sepsis （n = 59） or severe sepsis （n = 54）. However, in patients with sepsis, TLR4 level was significantly decreased from l0 days in simvastatin group as compared with that of conventional therapy group （n = 47）, and it was decreased up to 15 days [mean fluorescence intensity （MFI）： 21 （19, 28） vs. 27 （25, 33） at 10 days, Z = 2.198, P = 0.021; 16 （15, 21） vs. 26 （23, 34） at 15 days, Z = 4.611, P = 0.002]. In patients with severe sepsis, there was no significant difference in TLR4 level at different time points between simvastatin group and conventional treatment group （n = 38） [MFI： 55 （52, 63） vs. 56 （48, 65） at 1 day, Z = 0.313, P = 0.692; 47 （42, 56） vs. 49 （41, 58） at 5 days, Z = 0.827, P = 0.533; 40 （35, 42） vs. 42 （37, 45） at 10 days, Z = 1.012, P = 0.301; 33 （30, 38） vs. 38 （35, 41） at 15 days, Z = 0.539, P = 0.571]. No adverse reaction related with simvastatin was found during treatment in patients with sepsis or severe sepsis. Conclusions Statins could significantly down-regulate the TLR4 expression on peripheral blood monocytes in septic patients, while it showed no significant influence on TLR4 expression in patients with severe sepsis. A different effect of statins on TLR4 expression and the downstream inflammation process in sepsis and severe sepsis patients might partially explain the discrepancy in previous reports about the therapeutic effect of statins therapy in sepsis and severe sepsis patients.