重组尿激酶原治疗对大鼠肺血栓栓塞症后血浆纤溶因子的影响

Changes of plasma fibrinolytic factors in pulmonary thromboembolism rats after rcecombinant prourokinase treatment

目的观察重组尿激酶原(recombinant prourokinase,r Pro-UK)治疗大鼠肺血栓栓塞症(pulmonary tromboembolus,PTE)后血浆纤溶因子的变化及其意义。方法雄性SD大鼠28只,颈外静脉注入加热125-碘(125I)标记纤维蛋白原(Fib)自体血栓,复制大鼠PTE模型,随机分组如下:1正常对照组;2 PTE 5 d组,即在造模成功后观察5 d活杀;3 Pro-UK溶栓治疗组:分为多次给药亚组(PTE造模成功后第3天,予Pro-UK 1 mg/kg,后连续2 d给予Pro-UK 0.25 mg/kg,最后1 d给药2 h后与PTE 5 d组大鼠同时活杀)和单次给药亚组(PTE造模成功后第3天给予Pro-UK 1 mg/kg,后连续2 d给予生理盐水,活杀时间同PTE 5 d组大鼠)。每组7只,在实验结束时经颈动脉放血活杀动物,留取血浆标本测定尿激酶型纤溶酶原激活物(u-PA)、尿激酶型纤溶酶原激活物受体(u-PAR)、Fib的水平和α2-抗纤溶酶(α2-AP)的活性。结果 1多次给药亚组血浆u-PA、u-PAR水平较PTE 5 d组(Pu-PA<0.05,Pu-PAR<0.01)及单次给药亚组(Pu-PA<0.01,Pu-PAR<0.05)明显升高,与血栓溶解率正相关(ru-PA=0.766,P<0.05;ru-PAR=0.785,P<0.05)。2 r Pro-UK溶栓治疗后血浆Fib浓度和α2-AP活性与PTE 5 d组比较无显著差异(P>0.05)。结论 1 r Pro-UK溶栓治疗可促进内皮细胞合成和分泌u-PA、u-PAR,有助于血栓溶解,这可能是r Pro-UK的一个重要的溶栓机制。2 r Pro-UK多次给药方案治疗大鼠PTE没有引起继发全身纤溶激活,具有纤维蛋白特异性。

Objective To observe the changes in fibrinolytic factors in rats with pulmonary thromboembolism（PTE）after recombinanl prourokinase（rPro-UK） treatment and its significance.Methods PTE was induced in male SpragueDawley（SD） rats by injecting heated ^（125）iodine-labeled fibrinogen（Fib） autologous thromboemboli into external jugular veins.Twenty-eight rats were randomly assigned into following groups（7 rats each）：① healthy control group;② PTE 5 d group,the rats in which were sacrificed at 5 d after the PTE model was made;③ PTE3 d receiving rPro-UK thrombolytic treament groups including multibolus treatment sub group（rPro-UK was given in 1 mg/kg on the post-PTE third day followed by 2 consecutive days of a lower dose 0.25 mg/kg and rats were sacrificed 2 h after the last injection at the same time as PTE5 d group） and single bolus treatment sub group（rPro-UK was given in 1 mg/kg on the post-PTE third day followed by 2 consecutive days of 0.5 ml saline and rats were sacrificad at the same time as the former group）.The rats were quickly sacrificad at the fixed time through carotid bleeding and plasma samples were reserved for analysis of urokinase-type plasminogen activator（u-PA）,urokinase-type plasminogen activator receptor（u-PAR）,fibrinogen（Fib） andα_2-antiplasmin（α_2-AP）.Results CD Plasma concentrations of u-PA and u-PAR were increased were significantly in rProUK multibolus treatment sub group than in PTE 5 d group（P_（u-PA）0.05,P_（u-PAR）0.01）and rPro-UK single bolus treatment sub group（P_（u-PA）0.01,P_（u-PAR）0.05）,correlated with the thrombolysis rate in rPro-UK multibolus treatment sub group（r_（u-PA）=0.766,P〈0.05;r_（u-PAR）=0.785,P〈0.05）.② No difference of plasma Fib and α2-AP was seen between Pro-UK treatment groups and PTE 5 d group（P〈0.05）.Conclusion ① Plasma levels of endogenous u-PA and u-PAR are increased at different time points after PTE and are further enhanced after Pro-UK treatment,which promotes endogenous fibrinolysis and thrombus lysis.This is probably related to increased synthesis and secretion of endothelial cells which may be a key thrombolytic mechanism of Pro-UK.② Absence of systemic activation of the fibrinolytic system in Pro-UK multibolus treatment sub group means that the regimen is feasible and Prn-UK is fibrin specific.