戊二醛聚合猪血红蛋白氧载体安全性及有效性初步研究
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摘要
目的:研究戊二醛聚合猪血红蛋白分子量对血压的影响,并对其在大鼠失血性休克复苏中的功效进行初步研究。
方法:用浓度分别为90mg/mL,70mg/mL,50mg/mL的分子内交联的高氧亲和力(P_(50)均小于10mmHg)的64kDa血红蛋白对大鼠进行50%等容量换血,通过血压在换血前后的变化研究其对血压的影响以及在氧载体制品中所允许的安全剂量;并以相同的方法研究平均分子量分别为250kDa,500kDa,800kDa,1100kDa的高氧亲和力的聚合血红蛋白对血压的影响。
以自身全血回输作为阴性对照组;乳酸林格氏液,羟乙基淀粉和不复苏作为阳性对照组;浓度为90mg/mL,平均分子量为300kDa左右的高氧亲和力的聚合血红蛋白为实验组(n=6),对失血性休克的大鼠进行复苏。动态监测大鼠平均动脉血压,心率和心电图,并在大鼠基础、休克末、复苏后30min、60min、120min取动脉血测血气。综合比较各项指标对戊二醛聚合猪血红蛋白的抗休克性能进行评价。
结果:浓度为90mg/mL分子内交联四聚体血红蛋白(64kDa)在50%等容量换血实验中会使大鼠血压在换血过程中增加约20-25mmHg;浓度降低至70mg/mL和50mg/mL时,血压升高的现象基本消失,心率和血气各项指标均没有明显的变化。平均分子量为250kDa、500kDa的聚合血红蛋白在换血过程中以及换血完30min,大鼠血压比较平稳;800kDa和1100kDa的聚合血红蛋白在换血过程中部分大鼠血压出现下降的趋势,分子量越大出现血压下降的动物数量越多。大鼠失血性休克实验表明:戊二醛聚合猪血红蛋白同全血复苏的各项指标接近,MAP,HR,血气值均恢复到休克前的基础值,明显优于不复苏,乳酸林格氏液和羟乙基淀粉复苏的对照组。
结论:聚合血红蛋白的分子量和分子内交联的四聚体血红蛋白(64kDa)的含量均对等容量换血大鼠的血压有影响。浓度为90mg/mL的分子内交联的四聚体血红蛋白(64kDa)会使大鼠血压升高,但是当浓度小于50mg/mL时对大鼠血压基本没有影响;平均分子量在250kDa～500kDa的Poly-pHb对大鼠血压没有影响,较高分子量的Poly-pHb会引起血压的下降。用平均分子量为300kDa的戊二醛聚合猪血红蛋白进行大鼠失血性休克复苏,能够在短时间内有效恢复休克大鼠血容量,心率、血气等各项指标,是一种非常有开发前景的血红蛋白类氧载体制剂。
Objective: To investigate the response of blood pressure on molecular weight and the resuscitation of hemorrhagic shock on rats with glutaraldehyde-polymerized porcine hemoglobin (Poly-pHb).
Methods: SD male rats (295±15g) have been used to executing fifty percent isovolemic exchange transfusion transfusions by different concentration lower P_(50) intra-molecular cross-linked tetramer. The concentration of tetramer was 90mg/mL, 70mg/mL and 50mg/mL, respectively. Mean arterial pressure (MAP) was monitored continuously during the exchange transfusion and followed 30min.The content of tetramer was decided on the variation of the MAP. The same method has been used to studying different average molecular weight polymerized hemoglobin, including 250kDa, 500kDa, 800kDa, 1100kDa which are higher oxygen affinity have affected the Oxygen affinity. Blood has been drawn from femoral artery to inducing shock. The therapeutic effect of Poly-pHb was evaluated by comparing with other resuscitation fluids. After 30 minutes of ischemia , a kind of Poly-pHb (9mg/mL, P_(50)<10mmHg, MW=300kDa) was infused through the femoral vein as a treated group, and whole blood, Ringer's lactate and hydroxyethyl starch were infused respectively as the control group. Mean arterial blood pressure, heart rate and blood-gas were monitored at the time of baseline, end shock, 30 min, 60 min and 120 min after resuscitation, respectively.
Results: It is showed that the MAP had been increased by 90mg/mL tetramer up to 20-25mmHg during 50% isovolemic exchange transfusion, and it is also showed that the MAP had hardly effected by the concentration of tetramer lower than 50mg/mL. During the isovolemic exchange transfusions, the MAP maintained stabilization in the infusion which molecular weight were 250kDa and 500kDa, while the MAP was decreased in the infusion which molecular weight were 800kDa and 1100kDa. It is showed that Poly-pHb has the similar therapeutic effects on hemorrhagic shock when compared with the whole blood, but it is better than any other controls.
Conclusions: The MAP has been influenced by the concentration of tetramer and molecular weight in 50% isovolemic exchange transfusions. The blood pressure has been increased by the tetramer more than 90mg/mL, so we found the safety scope of concentration of tetramer is lower than 50mg/mL. And the MAP has been hardly influenced by the Poly-pHb with MW about 300kDa.While the MAP has been decreased by the additional MW of tetramer. The Poly-pHb is an effective therapeutic solution on hemorrhagic shock, and it is a perfect blood substitute in the future.
方法:用浓度分别为90mg/mL,70mg/mL,50mg/mL的分子内交联的高氧亲和力(P_(50)均小于10mmHg)的64kDa血红蛋白对大鼠进行50%等容量换血,通过血压在换血前后的变化研究其对血压的影响以及在氧载体制品中所允许的安全剂量;并以相同的方法研究平均分子量分别为250kDa,500kDa,800kDa,1100kDa的高氧亲和力的聚合血红蛋白对血压的影响。
以自身全血回输作为阴性对照组;乳酸林格氏液,羟乙基淀粉和不复苏作为阳性对照组;浓度为90mg/mL,平均分子量为300kDa左右的高氧亲和力的聚合血红蛋白为实验组(n=6),对失血性休克的大鼠进行复苏。动态监测大鼠平均动脉血压,心率和心电图,并在大鼠基础、休克末、复苏后30min、60min、120min取动脉血测血气。综合比较各项指标对戊二醛聚合猪血红蛋白的抗休克性能进行评价。
结果:浓度为90mg/mL分子内交联四聚体血红蛋白(64kDa)在50%等容量换血实验中会使大鼠血压在换血过程中增加约20-25mmHg;浓度降低至70mg/mL和50mg/mL时,血压升高的现象基本消失,心率和血气各项指标均没有明显的变化。平均分子量为250kDa、500kDa的聚合血红蛋白在换血过程中以及换血完30min,大鼠血压比较平稳;800kDa和1100kDa的聚合血红蛋白在换血过程中部分大鼠血压出现下降的趋势,分子量越大出现血压下降的动物数量越多。大鼠失血性休克实验表明:戊二醛聚合猪血红蛋白同全血复苏的各项指标接近,MAP,HR,血气值均恢复到休克前的基础值,明显优于不复苏,乳酸林格氏液和羟乙基淀粉复苏的对照组。
结论:聚合血红蛋白的分子量和分子内交联的四聚体血红蛋白(64kDa)的含量均对等容量换血大鼠的血压有影响。浓度为90mg/mL的分子内交联的四聚体血红蛋白(64kDa)会使大鼠血压升高,但是当浓度小于50mg/mL时对大鼠血压基本没有影响;平均分子量在250kDa～500kDa的Poly-pHb对大鼠血压没有影响,较高分子量的Poly-pHb会引起血压的下降。用平均分子量为300kDa的戊二醛聚合猪血红蛋白进行大鼠失血性休克复苏,能够在短时间内有效恢复休克大鼠血容量,心率、血气等各项指标,是一种非常有开发前景的血红蛋白类氧载体制剂。
Objective: To investigate the response of blood pressure on molecular weight and the resuscitation of hemorrhagic shock on rats with glutaraldehyde-polymerized porcine hemoglobin (Poly-pHb).
Methods: SD male rats (295±15g) have been used to executing fifty percent isovolemic exchange transfusion transfusions by different concentration lower P_(50) intra-molecular cross-linked tetramer. The concentration of tetramer was 90mg/mL, 70mg/mL and 50mg/mL, respectively. Mean arterial pressure (MAP) was monitored continuously during the exchange transfusion and followed 30min.The content of tetramer was decided on the variation of the MAP. The same method has been used to studying different average molecular weight polymerized hemoglobin, including 250kDa, 500kDa, 800kDa, 1100kDa which are higher oxygen affinity have affected the Oxygen affinity. Blood has been drawn from femoral artery to inducing shock. The therapeutic effect of Poly-pHb was evaluated by comparing with other resuscitation fluids. After 30 minutes of ischemia , a kind of Poly-pHb (9mg/mL, P_(50)<10mmHg, MW=300kDa) was infused through the femoral vein as a treated group, and whole blood, Ringer's lactate and hydroxyethyl starch were infused respectively as the control group. Mean arterial blood pressure, heart rate and blood-gas were monitored at the time of baseline, end shock, 30 min, 60 min and 120 min after resuscitation, respectively.
Results: It is showed that the MAP had been increased by 90mg/mL tetramer up to 20-25mmHg during 50% isovolemic exchange transfusion, and it is also showed that the MAP had hardly effected by the concentration of tetramer lower than 50mg/mL. During the isovolemic exchange transfusions, the MAP maintained stabilization in the infusion which molecular weight were 250kDa and 500kDa, while the MAP was decreased in the infusion which molecular weight were 800kDa and 1100kDa. It is showed that Poly-pHb has the similar therapeutic effects on hemorrhagic shock when compared with the whole blood, but it is better than any other controls.
Conclusions: The MAP has been influenced by the concentration of tetramer and molecular weight in 50% isovolemic exchange transfusions. The blood pressure has been increased by the tetramer more than 90mg/mL, so we found the safety scope of concentration of tetramer is lower than 50mg/mL. And the MAP has been hardly influenced by the Poly-pHb with MW about 300kDa.While the MAP has been decreased by the additional MW of tetramer. The Poly-pHb is an effective therapeutic solution on hemorrhagic shock, and it is a perfect blood substitute in the future.
引文
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