尿激酶联合低分子肝素对急性肺栓塞大鼠炎性反应及肺血流动力学的影响研究

Impact of Urokinase Combined with Low Molecular Weight Heparin on Inflammatory Response and Pulmonary Hemodynamics in Rats with Acute Pulmonary Embolism

背景急性肺栓塞(APE)是一种炎症浸润性疾病,可导致肺动脉压持续升高、肺血流动力学改变。低分子肝素(LMWH)和尿激酶(UK)是临床治疗APE的常用药物,但二者联合治疗效果尚未完全明确。目的探讨UK联合LMWH对APE大鼠炎性反应及肺血流动力学的影响。方法2018—2019年,将80只SD大鼠随机分为假手术(Sham)组、APE组、LMWH组、UK组及UK+LMWH组,每组16只。除Sham组外,其他组大鼠均采用自体血栓栓塞法制备APE模型;模型制备成功后,LMWH组大鼠皮下注射依诺肝素钠注射液,UK组大鼠静脉滴注UK,UK+LMWH组大鼠静脉滴注UK后皮下注射依诺肝素钠注射液,Sham组、APE组大鼠静脉滴注等量0.9%氯化钠溶液。比较各组干预8、72 h血清炎性因子〔包括白介素1β(IL-1β)、白介素8(IL-8)及肿瘤坏死因子α(TNF-α)〕、肺血流动力学指标〔包括平均肺动脉压(mPAP)和右心室压力(RVP)〕及血气指标〔包括动脉血氧分压(PaO2)和动脉血二氧化碳分压(PaCO2)〕。结果干预8、72 h,LMWH组和UK组血清IL-1β、IL-8、TNF-α水平高于Sham组,但低于APE组(P<0.05)。干预8 h UK+LMWH组血清IL-1β水平低于APE组(P<0.05);干预72 h UK+LMWH组血清IL-1β水平高于Sham组,但低于APE组(P<0.05)。干预8 h UK+LMWH组血清IL-8水平低于APE组和LMWH组(P<0.05);干预72 h UK+LMWH组血清IL-8水平高于Sham组,但低于APE组、LMWH组、UK组(P<0.05)。干预8、72 h,UK+LMWH组血清TNF-α水平高于Sham组,但低于APE组、LMWH组、UK组(P<0.05)。干预8、72 h,LMWH组和UK组mPAP、RVP高于Sham组,但低于APE组(P<0.05);干预8、72 h,LMWH组和UK组PaO2低于Sham组,但高于APE组(P<0.05)。干预8 h UK+LMWH组mPAP高于Sham组,但低于APE组和LMWH组(P<0.05);干预72 h UK+LMWH组mPAP高于Sham组,但低于APE组(P<0.05)。UK+LMWH组干预8 h RVP低于APE组和LMWH组,干预72 h RVP低于APE组(P<0.05)。干预8 h UK+LMWH组PaO2低于Sham组,但高于APE组和LMWH组(P<0.05);干预72 h UK+LMWH组PaO2高于APE组、LMWH组及UK组(P<0.05)。结论UK联合LMWH能有效减轻APE大鼠炎性反应,改善肺血流动力学及换气功能,且效果优于单用UK及LMWH。

Background Acute pulmonary embolism(APE)is an inflammatory infiltrative disease,which can lead to continuous increase of pulmonary arterial pressure and pulmonary hemodynamic changes.Objective To investigate the impact of urokinase(UK)combined with low molecular weight heparin(LMWH)on the inflammatory response and pulmonary hemodynamics in rats with APE.Methods From 2018 to 2019,80 SD rats were randomly divided into Sham group,APE group,LMWH group,UK group and UK+LMWH group,with 16 rats in each group.Except for Sham group,APE models were established by autologous thromboembolism in other groups;after the APE model was successfully prepared,rats in LMWH group were subcutaneously injected with enoxaparin injection,rats in UK group were intravenously injected with UK,rats in UK+LMWH group were intravenously injected with UK and then subcutaneously with enoxaparin injection,rats in Sham group and APE group were intravenously injected with same amount of 0.9%sodium chloride solution.Serum inflammatory factors〔including interleukin-1β(IL-1β),interleukin-8(IL-8)and tumor necrosis factor-α(TNF-α)〕,pulmonary hemodynamic indexes〔including mean pulmonary artery pressure(mPAP)and right ventricular pressure(RVP)〕,and blood gas indexes(including PaO2 and PaCO2)were compared among the groups at 8 and 72 hours after intervention.Results 8 and 72 hours after intervention,the serum levels of IL-1β,IL-8 and TNF-αin LMWH group and UK group were higher than those in Sham group,but lower than those in APE group(P<0.05).8 hours after intervention,the serum level of IL-1βin UK+LMWH group was lower than that in APE group(P<0.05);72 hours after intervention,the serum level of IL-1βin UK+LMWH group was higher than that in Sham group,but lower than that in APE group(P<0.05).8 hours after intervention,the serum level of IL-8 in UK+LMWH group was lower than that in APE group and LMWH group(P<0.05);72 hours after intervention,the serum level of IL-8 in UK+LMWH group was higher than that in Sham group,but lower than that in APE group,LMWH group and UK group(P<0.05).8 and 72 hours after intervention,the serum level of TNF-αin UK+LMWH group was higher than that in Sham group,but lower than that in APE group,LMWH group and UK group(P<0.05).8 and 72 hours after intervention,the mPAP and RVP in LMWH group and UK group were higher than those in Sham group,but lower than those in APE group(P<0.05);and PaO2 in LMWH group and UK group was lower than that in Sham group,but higher than that in APE group(P<0.05).8 hours after intervention,the mPAP in UK+LMWH group was higher than that in Sham group,but lower than that in APE group and LMWH group(P<0.05);72 hours after intervention,the mPAP in UK+LMWH group was higher than that in Sham group,but lower than that in APE group(P<0.05).The RVP in UK+LMWH group was lower than that in APE group and LMWH group 8 hours after intervention,and the RVP in UK+LMWH group was lower than that in APE group 72 hours after intervention(P<0.05).8 hours after intervention,the PaO2 in UK+LMWH group was lower than that in Sham group,but higher than that in APE group and LMWH group(P<0.05);72 hours after intervention,the PaO2 in UK+LMWH group was higher than that in APE group,LMWH group and UK group(P<0.05).Conclusion UK combined with LMWH can effectively reduce the inflammatory reaction,improve pulmonary hemodynamics and ventilation function in APE rats,and the effect is better than that of UK and LMWH alone.