右美托咪定对大鼠内毒素性急性肺损伤时miR-155-HIF—1α—HO-1信号通路的影响

Effect of dexmedetomidine on microRNA-155-hypoxia-inducible factor-1α-heme oxygenase-1 signaling pathway in a rat model of endotoxin-induced acute lung injury

目的评价右美托咪定对大鼠内毒素性急性肺损伤时微小RNA（miRNA）-155-缺氧诱导因子-1α（HIF-1α）-血红素加氧酶-1（HO-1）信号通路的影响。方法清洁级健康成年雄性Wistar大鼠40只，体重220～250g，采用随机数字表法分为4组（n=10）：对照组（C组）、右美托咪定组（D组）、内毒素性急性肺损伤组（L组）、内毒素性急性肺损伤＋右美托咪定组（LD组）。L组和LD组腹腔注射内毒素5mg／kg。D组和LD组腹腔注射生理盐水或内毒素前静脉输注右美托咪定负荷剂量1μg·kg^-1·h^-1.min，随后调整右美托咪定剂量为5μg·kg^-1·h^-1。腹腔注射内毒素或生理盐水后6h时采集颈动脉血样，测定PaO2，收集支气管肺泡灌洗液（BALF），测定总蛋白、IL-1β、TNF—α和细胞间黏附分子-1（ICAM-1）的浓度；随后处死大鼠取肺，称重后计算肺湿干重（W／D）比值，检测肺miR-155、IL-1β、TNF-α和ICAM-1的mRNA、HIF-1α和HO-1的表达水平，观察病理学结果并行肺损伤评分。结果与C组比较，L组和LD组PaO2降低，W／D比值、肺损伤评分、BALF总蛋白浓度、IL-1β、TNF—α及ICAM-1浓度、肺miR-155、IL-16、TNF—α和ICAM-1的mRNA、HIF-1α和HO-1表达水平升高（P〈0．05）；与L组比较，LD组PaO2、肺HIF—1α和HO-1表达升高，W／D比值、肺损伤评分、BALF总蛋白、IL-1β、TNF—α及ICAM-1浓度、肺miR-155、IL-1β、TNF—α．和ICAM-1的mRNA表达水平降低（P〈0．05）。结论右美托咪定通过调控miR-155-HIF-1α．HO-1信号通路减轻大鼠内毒素性急性肺损伤。

Objective To evaluate the effect of dexmedetomidine on microRNA （miRNA）-155- hypoxia-inducible factor-1α （HIF-1α）-heme oxygenase-1 （HO-1） signaling pathway in a rat model of endotoxin-induced acute lung injury. Methods Forty adult male Wistar rats, weighing 220-250 g, were equally and randomly divided into 4 groups using a random number table： control group （group C）, dexmedetomidine group （group D ）, endotoxin-induced acute lung injury group （group L）, and endotoxin-induced acute lung injury＋dexmedetomidine group （group LD）. Acute lung injury was induced by intraperitoneal lipopolysaccharide （LPS） 5 mg/kg in L and LD groups. In D and LD groups, dexmedetomidine was infused in a loading dose of μg·kg^-1·h^-1 for 10 rain starting before intraperitoneal injection of normal saline or LPS followed by an infusion of 5 μg·kg^-1·h^-1 throughout the operation. At 6 h after normal saline or LPS injection, blood samples were taken from the carotid artery for detection of arterial oxygen partial pressure （PaO2 ）. The left lung was lavaged, and broncho-alveolar lavage fluid （BALF） was collected for determination of concentrations of total protein, interleukin-1β （IL-1β）, tumor necrosis factor-α （TNF-α）, and intercellular adhesion molecule-1 （ICAM-1）. The rats were then sacrificed, and lungs were removed for determination of the wet to dry lung weight ratio （ W/D ratio） , mRNA expression of miR-155, IL-1β, TNF-α and ICAM-1, and protein expression of HIF-1α and HO-1, and for examination of the pathological changes which were scored. Results Compared with group C, the PaO2 was significantly decreased, and the W/D ratio, lung injury score, concentrations of total protein, IL-1β, TNF-α and ICAM-1 in BALF, mRNA expression of miR-155, IL-1β, TNF-α and ICAM-1, and protein expression of HIF-1α and HO-1 were significantly increased in L and LD groups （ P 〈 0.05）. Compared with group L, the PaO2 and protein expression of HIF-1α and HO-1 were significantly increased, and the W/D ratio, lung injury score, concentrations of total protein, IL-1β, TNF-α and ICAM-1 in BALF, and mRNA expression of miR-155, IL-1β, TNF-α and ICAM-1 were significantly decreased in group LD （P〈0.05）. Conclusion Dexmedetomidine reduces endotoxin-induced acute lung injury through activating miR-155-HIF-1α-HO-1 signaling pathway in rats.