右美托咪定对慢性阻塞性肺损伤大鼠模型的保护作用与机制研究
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摘要
目的探讨右美托咪定(DEX)对慢性阻塞性肺损伤(COPD)大鼠模型的保护作用及机制。方法气道内滴注脂多糖联合烟熏28天构建COPD大鼠模型,大鼠分为4组,即对照组、COPD组、COPD+DEX组和COPD+DEX+EX527组。检测大鼠的肺功能、肺泡灌洗液中炎症细胞和因子含量、肺组织形态结构、NLRP3炎症体和沉默信息调节因子1 (SIRT1)信号通路相关蛋白的表达。结果与COPD组相比较,COPD+DEX组大鼠的0. 3秒用力呼气量占用力肺活量比值和呼气峰流速升高(P <0. 01);肺泡平均截距降低(P<0. 01);肺泡灌洗液中白细胞总数、中性粒细胞比例、IL-1β和TNF-α含量降低(P <0. 01);肺组织中NLRP3、Cleaved caspase-1和ASC蛋白的表达降低(P <0. 01);肺组织中SIRT1蛋白的表达升高,Ac-FOXO1蛋白的表达降低(P <0. 01)。SIRT1抑制剂EX527可以不同程度的阻断DEX的上述治疗效应。结论在COPD大鼠模型中,右美托咪定可以降低肺泡腔扩大,抑制中性粒细胞浸润和NLRP3炎性体表达,其保护作用可能与SIRT1信号通路的激活有关。
Objective To explore the protective effect and mechanism of dexmedetomidine( DEX) on chronic obstructive pulmonary injury( COPD) rats. Methods COPD rat model was established by intratracheal lipopolysaccharide infusion combined with smoking for 28 days. The rats were divided into four groups: the control group,the COPD group,the COPD + DEX group and the COPD + DEX + EX527 group. The pulmonary function,inflammatory cells and cytokines in alveolar lavage fluid,lung tissue morphology,the expression of NLRP3 inflammatory body and SIRT1 signaling pathway were detected. Results Compared with the control group,DEX treatment increased FEV0. 3/FVC and PEF,and reduced mean linear intercept of alveolus. DEX treatment decreased the total number of white blood cells,the proportion of neutrophils,the content of IL-1β and TNF-α in bronchoalveolar lavage fluid.DEX treatment also reduced the expression of NLRP3,Cleaved caspase-1,ASC and Ac-FOXO1 and increased the expression of SIRT1 protein in lung tissue. EX527 and a SIRT1 inhibitor could block these therapeutic effect of DEX to different degrees. Conclusion In the COPD rat model,dexmedetomidine can reduce alveolar enlargement,inhibit neutrophil infiltration and NLRP3 inflammatory body expression. The protective effect may be related to the activation of SIRT1 signaling pathway.
Objective To explore the protective effect and mechanism of dexmedetomidine( DEX) on chronic obstructive pulmonary injury( COPD) rats. Methods COPD rat model was established by intratracheal lipopolysaccharide infusion combined with smoking for 28 days. The rats were divided into four groups: the control group,the COPD group,the COPD + DEX group and the COPD + DEX + EX527 group. The pulmonary function,inflammatory cells and cytokines in alveolar lavage fluid,lung tissue morphology,the expression of NLRP3 inflammatory body and SIRT1 signaling pathway were detected. Results Compared with the control group,DEX treatment increased FEV0. 3/FVC and PEF,and reduced mean linear intercept of alveolus. DEX treatment decreased the total number of white blood cells,the proportion of neutrophils,the content of IL-1β and TNF-α in bronchoalveolar lavage fluid.DEX treatment also reduced the expression of NLRP3,Cleaved caspase-1,ASC and Ac-FOXO1 and increased the expression of SIRT1 protein in lung tissue. EX527 and a SIRT1 inhibitor could block these therapeutic effect of DEX to different degrees. Conclusion In the COPD rat model,dexmedetomidine can reduce alveolar enlargement,inhibit neutrophil infiltration and NLRP3 inflammatory body expression. The protective effect may be related to the activation of SIRT1 signaling pathway.
引文
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[2] DEMURO J P,MONGELLI M N,HANNA A F. Use of dexmedetomidine to facilitate non-invasive ventilation[J]. Int J Crit Illn Inj Sci,2013,3(4):274-275.
[3] ZHANG Y,JIA S,GAO T,et al. Dexmedetomidine mitigate acute lung injury by inhibiting IL-17-induced inflammatory reaction[J].Immunobiology,2018,223(1):32-37.
[4] LI N,OUYANG B S,LIU L,et al. Dexmedetomidine protected COPD-induced lung injury by regulating miRNA-146a[J]. Bratisl Lek Listy,2016,117(9):539-542.
[5] MENG L,LI L,LU S,et al. The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-κB and PI3K/Akt/m TOR pathways[J]. Mol Immunol,2018,94:7-17.
[6] YU L,LI S,TANG X,et al. Diallyl trisulfide ameliorates myocardial ischemia-reperfusion injury by reducing oxidative stress and endoplasmic reticulum stress-mediated apoptosis in type 1 diabetic rats:role of SIRT1 activation[J]. Apoptosis,2017,22(7):942-954.
[7] WANG C,DING H,TANG X,et al. Effect of Liuweibuqi Capsules in Pulmonary Alveolar Epithelial Cells and COPD Through JAK/STAT Pathway[J]. Cell Physiol Biochem,2017,43(2):743-756.
[8] CHEN C M,CHOU H C. Human mesenchymal stem cells attenuate hyperoxia-induced lung injury through inhibition of the renin-angiotensin system in newborn rats[J]. Am J Transl Res,2018,10(8):2628-2635.
[9] PAUWELS N S,BRACKE K R,DUPONT L L,et al. Role of IL-1αand the Nlrp3/caspase-1/IL-1βaxis in cigarette smoke-induced pulmonary inflammation and COPD[J]. Eur Respir J,2011,38(5):1019-1028.
[10] WANG Y,HE J,LIAO M,et al. An overview of Sirtuins as potential therapeutic target:structure,function and modulators[J]. Eur J Med Chem,2019,161:48-77.
[11] YANAGISAWA S,PAPAIOANNOU A I,PAPAPORFYRIOU A,et al. Decreased Serum Sirtuin-1 in COPD[J]. Chest,2017,152(2):343-352.