右美托咪定对小鼠内毒素性急性肺损伤时JAK2/STAT3信号通路的影响

Effect of dexmedetomidine on JAK2/STAT3 signaling pathway in mice with endotoxin-induced acute lung injury

目的 评价右美托咪定对小鼠内毒索性急性肺损伤时蛋白酪氨酸激酶2（JAK2）/信号转导和转录激活因子3（STAT3）信号通路的影响.方法 清洁级健康雄性成年C57BL/6小鼠24只,体重20～25 g.采用随机数字表法分为3组（n=8）：对照组（C组）、内毒素性急性肺损伤组（ALI组）和右美托咪定组（Dex组）.采用腹腔注射脂多糖（LPS）5 mg/kg的方法制备小鼠内毒素性急性肺损伤模型.Dex组于注射LPS后1h时腹腔注射右美托咪定40 μg/kg,C组和ALI组给予等容量生理盐水.腹腔注射LPS后6h,采集颈动脉血样测定PaO2,随后处死动物,收集支气管肺泡灌洗液（BALF）,测定BALF总蛋白、IL-1β、IL-6及TNF-α的浓度;取肺组织称重,计算肺湿重/干重（W/D）比值,检测磷酸化JAK2（p-JAK2）及磷酸化STAT3（p-STAT3）、IL-1β mRNA、IL-6 mRNA和TNF-α mRNA的表达,观察病理学结果并进行肺损伤评分.结果 与C组比较,ALI组和Dex组PaO2降低、肺W/D比值、肺损伤评分、BALF总蛋白、IL-1β、IL-6及TNF-α、肺组织IL-1β、IL-6和TNF-α的mRNA、p-JAK2和p-STAT3表达水平升高（P＜0.05）;与ALI组比较,Dex组PaO2升高、肺W/D比值、肺损伤评分、BALF总蛋白、IL-1β、IL-6及TNF-α、肺组织IL-1β、IL-6和TNF-α的mRNA、p-JAK2和p-STAT3表达水平降低（P＜0.05）.结论 右美托咪定减轻小鼠内毒素性急性肺损伤的机制可能与抑制JAK2/STAT3信号通路激活有关.

Objective To evaluate the effect of dexmedetomidine on janus kinase 2/signal transducer and activator of transcription 3 （JAK2/STAT3） signaling pathway in mice with endotoxin-induced acute lung injury （ALI）.Methods Twenty-four male C57BL/6 mice,weighing 20-25 g,were randomly divided into 3 groups （n=8 each） using a random number table：control group （group C）,endotoxin-induced ALI group （group ALI）,and dexmedetomidine group （group Dex）.ALI was induced with lipopolysaccharide （LPS） 5 mg/kg injected intraperitoneally.Dexmedetomidine 40 μg/kg was injected intraperitoneally at 1 h after LPS injection in group Dex,while the equal volume of normal saline was given in C and ALI groups.At 6 h after LPS injection,blood samples were collected from the carotid artery to detect arterial oxygen partial pressure （PaO2）.The mice were then sacrificed,and broncho-alveolar lavage fluid （BALF） was collected for determination of the concentrations of total protein,interleukin-1β （IL-1β）,IL-6 and tumor necrosis factor-or （TNF-α）.The lung tissues were removed for determination of wet to dry lung weight ratio （W/D ratio）,and expression of phosphorylated JAK2 （p-JAK2）,phosphorylated STAT3 （p-STAT3）,IL-1β mRNA,IL-6 mRNA and TNF-α mRNA,and for examination of the pathological changes which were scored.Results Compared with group C,the PaO2 was significantly decreased,and W/D ratio,lung injury score,concentrations of total protein,IL-1β,IL-6 and TNF-α in BALF,and expression of IL-1β,IL-6 and TNF-α mRNA,p-JAK2 and p-STAT3 were increased in ALI and Dex groups （P〈0.05）.Compared with group ALI,the PaO2 was significantly increased,and W/D ratio,lung injury score,concentrations of total protein,IL-1β,IL-6 and TNF-α in BALF,and expression of IL-1β,IL-6 and TNF-α mRNA,p-JAK2 and p-STAT3 were decreased in group Dex （P〈0.05）.Conclusion The mechanism by which dexmedetomidine attenuates LPS-induced ALI is probably related to inhibition of activation of JAK2/STAT3 signaling pathway in mice.