抑制白三烯介导的炎症反应改善新生鼠急性肺损伤和支气管肺发育不良

Inhibition of leukotriene-mediated inflammatory response improves acute lung injury and bronchopulmonary dysplasia in neonatal rats

目的:探究5-脂氧酶抑制剂齐留通和白三烯受体拮抗剂孟鲁司特缓解脂多糖(LPS)诱导的新生大鼠急性肺损伤(ALI)和支气管肺发育不良(BPD)病理变化的效果。方法:新生大鼠分为对照组、二甲基亚砜(DMSO)对照组、模型组(LPS组)、LPS+孟鲁司特组、LPS+齐留通组。对照组为正常新生Wistar大鼠娩出后给予0.9%NaCl、DMSO;模型组为Wistar大鼠孕20及21天连续2 d腹腔注射LPS(2.5 mg/kg),干预组为模型鼠娩出后给予孟鲁司特、齐留通10 mg/kg,隔天一次腹腔注射,直至生后14 d。观察各组幼鼠出生24 h内、生后第7、14天肺组织病理改变,检测白三烯合成酶5-脂氧合酶(5-LO)及白三烯受体1(CysLTR1)在肺组织中的表达,ELISA检测肺泡灌洗液中LTB4和细胞因子IL-1β、IL-6、TNF-α的含量变化。结果:成功构建ALI和BPD模型鼠,观察到ALI和BPD模型鼠肺组织中5-LO、CysLTR1 mRNA和蛋白质表达量增高,肺泡灌洗液中LTB4以及促炎因子IL-1β、IL-6、TNF-α含量升高。齐留通组5-LO表达量下降,LTB4及IL-1β、IL-6、TNF-α含量下降;孟鲁司特组CysLTR1表达量和LTB4含量与模型组无差异,IL-1β、IL-6、TNF-α含量下降;齐留通组和孟鲁司特组肺组织病变较LPS组改善。结论:5-脂氧酶抑制剂和白三烯受体拮抗剂可减轻ALI以及BPD病理变化。

Objective:To explore the therapeutic effect of anti-leukotriene drugs zileuton and montelukast on lipopolysaccharide(LPS)induced acute lung injury(ALI)and bronchopulmonary dysplasia(BPD)in neonatal rats.Methods:The newborn rats were divided into the control group,the dimethyl sulfoxide(DMSO)group,the LPS model group,the LPS+montelukast group,and the LPS+zileuton group.The control group was given 0.9%NaCl and DMSO after normal newborn Wistar rats were delivered;the model group was intraperitoneally injected with LPS(2.5 mg/kg)on the 20th and 21st days of pregnancy for consecutive two days,and the intervention group was given montelukast and zileuton at 10 mg/kg intraperitoneally every other day after the delivery of the model rats until postna-tal day 14.The pathological changes of lung tissue of rats in each group within 24 hours of birth,7days,and 14 days after birth were observed,and the expression of leukotriene synthase 5-lipoxygenase(5-LO)and leukotriene receptor 1(CysLTR1)in lung tissue was detected.Also,the content of the LTB4,cytokine IL-1β,IL-6,and TNF-αin alveolar lavage fluid was detected.Results:The ALI and BPD models of rats were successfully constructed.It was observed that the expression of 5-LO and CysLTR1 mRNA and protein in the lung tissues of ALI and BPD rats increased,and LTB4 and pro-inflammatory factors IL-1β,IL-6,and TNF-αin alveolar lavage fluid increased too.The expres-sion of 5-LO in the zileuton group decreased and the content of LTB4,IL-1β,IL-6,and TNF-αde-creased too.No difference was found in the expression of CysLTR1 and the content of LTB4 be-tween the montelukast group and the model group,while the contents of IL-1β,IL-6,and TNF-αde-creased in the montelukast group.The pathological changes of lung tissue in the zileuton and montelu-kast groups improved.Conclusion:Anti-leukotriene drugs montelukast and zileuton may improve symptoms of acute lung injury and bronchopulmonary dysplasia in newborn rats.