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目的 探讨右美托咪定镇静对脓毒症合并急性呼吸窘迫综合征(ARDS)患者肺保护作用的机制.方法 选择2013年9月至2017年6月广西医科大学第一附属manbet官网登录 重症医学科(ICU)收治的脓毒症并发ARDS的成人患者,纳入氧合指数(PaO2/FiO2)150~200 mmHg(1 mmHg=0.133 kPa)、急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分10~20分、需要机械通气治疗>72 h者.按随机数字表法将患者分为无镇静组、丙泊酚组(0.3~4.0 mg·kg-1·h-1)和右美托咪定组(0.2~0.7 μg·kg-1·h-1),每组80例.3组均应用瑞芬太尼充分镇痛;镇静目标为Richmond躁动-镇静评分(RASS)-1~0分.各组分别于镇静前及镇静24、48、72 h取中心静脉血,采用酶联免疫吸附试验(ELISA)检测血清白细胞介素-6(IL-6)和肿瘤坏死因子-α (TNF-α)水平;于镇静前和镇静72 h取肺泡灌洗液,采用蛋白质免疫印迹试验(Western Blot)检测肺泡脱落细胞炎症信号途径及抗凋亡途径信号蛋白表达.结果 无镇静组治疗前后血清炎性因子以及肺泡脱落细胞炎症信号途径和抗凋亡途径信号蛋白表达均无明显变化.丙泊酚组和右美托咪定组镇静后血清IL-6、TNF-α水平以及肺泡细胞中Toll样受体4(TLR4)、髓样分化因子88(MyD88)和磷酸化c-Jun氨基末端激酶(p-JNK)蛋白表达均较镇静前明显下降,且右美托咪定组较丙泊酚组下降更为明显〔48 h:TNF-α(ng/L)为153.76±29.16比179.82±30.28;72 h:IL-6(ng/L)为272.18±42.76比304.49±44.93,TNF-α(ng/L)为102.18±30.25比140.28±28.92,TLR4(IA值)为0.288±0.034比0.648±0.029,MyD88(IA值)为0.356±0.030比0.752±0.044, p-JNK(IA值)为0.256±0.027比0.303±0.034,均1<0.05〕.丙泊酚组和右美托咪定组镇静后肺泡细胞中磷酸化蛋白激酶B(p-Akt)蛋白表达均较镇静前明显升高,且右美托咪定组p-Akt表达较丙泊酚组升高更为明显(IA值:1.032±0.030比0.743±0.028,1<0.05).结论 右美托咪定镇静可减轻脓毒症合并ARDS患者肺损伤时的炎症反应,可能依赖于TLR4-MyD88-JNK信号途径.

Objective To investigate the mechanisms of protective effects of dexmedetomidine on lungs in patients of sepsis complicated with acute respiratory distress syndrome (ARDS). Methods The adult patients with sepsis complicated with ARDS, the oxygenation index (PaO2/FiO2) was 150-200 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluationⅡ (APACHEⅡ) score was 10-20, need mechanical ventilation (MV) treatment > 72 hours, and admitted to intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from September 2013 to June 2017 were enrolled. According to the random number table method, the patients were divided into three groups (n = 80): no sedation group, propofol group (0.3-4.0 mg·kg-1·h-1) and dexmedetomidine group (0.2-0.7 μg·kg-1·h-1). The three groups were adequately analgesic treated with remifentanil. The sedation target was -1-0 of Richmond agitation-sedation score (RASS). The levels of interlenkin-6 (IL-6) and tumor necrosis factor-α (INF-α) were determined by enzyme linked immunosorbent assay (ELISA) before sedation, and 24, 48, 72 hours after sedation. The expressions of inflammatory signaling proteins in bronchoalveolar lavage fluid (BALF) were determined by Western Blot before sedation and 72 hours after sedation. Results There were no significant changes for inflammatory factors in serum, and inflammatory signaling proteins and anti-apoptotic signaling proteins in alveolar exfoliated cells in no sedation group. The levels of IL-6 and TNF-α in serum and the expressions of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and phosphorylated c-Jun N-terminal kinase (p-JNK) in alveolar cells in propofol group and dexmedetomidine group were all significantly reduced after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group [48 hours: TNF-α (ng/L) was 153.76±29.16 vs. 179.82±30.28;72 hours: IL-6 (ng/L) was 272.18±42.76 vs. 304.49±44.93, TNF-α (ng/L) was 102.18±30.25 vs. 140.28±28.92, TLR4 (IA value) was 0.288±0.034 vs. 0.648±0.029, MyD88 (IA value): 0.356±0.030 vs. 0.752±0.044, p-JNK (IA value): 0.256±0.027 vs. 0.303±0.034, all 1 < 0.05]. The expression of p-Akt in alveolar cells in propofol group and dexmedetomidine group was all significant increased after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group (IA value: 1.032±0.030 vs. 0.743±0.028, 1 < 0.05). Conclusion Dexmedetomidine exerts the protective effects on lungs in patients of sepsis complicated with ARDS through the TLR4-MyD88-JNK signaling pathway.