摘要
目的:探讨右美托咪定对高氧诱导急性肺损伤小鼠的保护作用及核转录因子红细胞系2p45相关因子2(Nrf2)/血红素加氧酶-1(HO-1)通路的影响。方法:将100只C57BL/6小鼠随机分为5组:正常对照组、模型组、地塞米松组(100 mg·kg-1)、右美托咪定低(40 mg·kg-1)、高(80 mg·kg-1)剂量组。除正常对照组外,其余各组建立高氧诱导急性肺损伤模型,并于造模成功后腹腔注射相应药物,正常对照组和模型组给予等体积生理盐水,qd,持续7 d。实验结束后,检测小鼠肺/体比值、肺损伤评分、血氧分压(Pa O2),小鼠肺组织中Nrf2、HO-1 mRNA及蛋白表达水平,胱天蛋白酶-1(caspase-1)、白细胞介素-1β(IL-1β)、白细胞介素-18(IL-18)蛋白水平。制作肺部HE染色切片,观察肺损伤情况。结果:与正常对照组比较,模型组肺/体比值、肺损伤评分、Nrf2 mRNA及蛋白表达水平、IL-1β、IL-18、caspase-1蛋白表达水平明显升高,Pa O2、HO-1 mRNA及蛋白表达水平明显降低(P<0.05);与模型组比较,右美托咪定组肺/体比值、肺损伤评分、Nrf2 mRNA及蛋白表达水平、IL-1β、IL-18、caspase-1蛋白表达水平明显降低,Pa O2、HO-1 mRNA及蛋白表达水平明显升高(P<0.05),且呈剂量相关性;右美托咪定低剂量组与地塞米松组比较差异有统计学意义(P<0.05)。正常对照组肺泡组织结构正常,无炎症细胞浸润、无胶原蛋白沉淀;模型组、右美托咪定低剂量组肺泡壁明显增厚、破裂,可见中性细胞及少量嗜酸性细胞浸润,肺间质可见较多胶原蛋白沉淀;右美托咪定高剂量组及地塞米松组肺泡结构基本正常,有少量中性细胞侵润,几乎无胶原蛋白沉淀。结论:右美托咪定对高氧诱导急性肺损伤小鼠的保护作用与抑制Nrf2 mRNA及蛋白表达水平表达,进而抑制IL-1β、IL-18、caspase-1蛋白表达有关。
Objective: To investigate the protective effect of dexmedetomidine in mice with acute lung injury induced by hyperoxia and the effect on the transcription nuclear factor erythroid 2-related factor 2( Nrf2)/hemeoxy genase 1( HO-1) pathway. Methods:Totally 100 C57 BL/6 mice were randomly divided into 5 groups: the normal control group,the model group,dexamethasone group( 100 mg·kg-1),and dexmedetomidine low( 40 mg·kg-1) and high( 80 mg·kg-1) dose groups. Except for the normal control group,the other groups established a model of hyperoxia-induced acute lung injury,the corresponding drug was intraperitoneally injected after the successful modeling,and the normal control group and the model group were given an equal volume of normal saline. At the end of the experiment,the lung/body ratio,lung injury score and blood oxygen partial pressure( Pa O2) were detected in mice;the expressions of Nrf2,HO-1 mRNA and protein,and the levels of caspase-1,interleukin-1β( IL-1β) and interleukin-18( IL-18) protein were detected in lung tissue of mice. Lung HE staining section was made to observe the lung injury. Results: Compared with those in the normal control group,the lung/body ratio,lung injury score,the expressions of Nrf2 mRNA and protein,the levels of IL-1β,IL-18 and caspase-1 protein were significantly increased in the model group,Pa O2 level and the expressions of HO-1 mRNA and protein were significantly decreased( P < 0. 05). Compared with those in the model group,the lung/body ratio,lung injury score,the expressions of Nrf2 mRNA and protein,the levels of IL-1β,IL-18 and caspase-1 protein were significantly decreased in dexmedetomidine groups,Pa O2 level and the expressions of HO-1 mRNA and protein were significantly increased( P < 0. 05),there was a dose-effect correlation,and there were significant differences between dexmedetomidine low dose group and dexamethasone group( P < 0. 05). The alveolar tissue structure of the normal control group was normal without inflammatory cell infiltration or collagen precipitation. The alveolar wall in the model group and dexmedetomidine low dose group was obviously thicker and ruptured with infiltration of neutral cells and a small number of eosinophils,and more collagen precipitation in pulmonary interstitium. The alveolar structure in dexmedetomidine high dose group and dexamethasone group was basically normal with a small number of neutrophils invading and without collagen precipitation. Conclusion: The protective effect of dexmedetomidine in mice with acute lung injury induced by hyperoxia is related to the inhibition of mRNA and protein expression level of Nrf2,which can further inhibit the protein expression levels of IL-1Β,IL-18 and Caspase-1.
作者
符新春
陶敏
徐晖
杨亦平
Fu Xinchun;Tao Min;Xu Hui;Yang Yiping(Department of Anesthesiology, Taizhou First People's Hospital, Zhejiang Taizhou 318020, China)
出处
《中国药师》
CAS
2019年第10期1805-1810,共6页
China Pharmacist
