重组人粒细胞集落刺激因子（rhG-CSF）对中子重度骨髓型急性放射病比格犬的实验治疗研究
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摘要
当前,世界各有核国家继续坚持核威慑的核心思想,认为核武器是维护国家安全和利益的重要保障,无核国家也正在极力发展核武器,我国受周边国家核武器的威胁逐渐增加。其次,当前恐怖活动猖獗,恐怖分子使用简易爆炸装置破坏核设施的可能性也随时存在。此外,核能和核技术应用过程中因操作失误等导致的临界事故也时有发生。不论是核武器爆炸还是重大核辐射事故均可导致大量人群受到不同比例中子和γ射线混合照射。研究表明,中子比例越高损伤效应越重。为做好核辐射突发事件医学应急准备,开展高比例中子-γ射线混合照射所致急性放射病(acute radiation sickness, ARS)的实验治疗研究具有重大的军事和社会意义。
众所周知,造血损伤是骨髓型ARS的基本损伤。目前,利用基因工程重组技术制备的重组造血生长因子已成为促进ARS造血功能恢复治疗中的首选药物。其中重组人粒细胞集落刺激因子(rhG-CSF)具有促进骨髓造血细胞增殖分化形成粒细胞集落、诱导中性粒细胞终末分化和增强中性粒细胞功能等作用,用于γ射线所致骨髓型ARS具有良好的治疗效果,成为国际公认的ARS治疗药物之一。但关于rhG-CSF对中子重度以上骨髓型ARS的治疗效果尚未见文献报道。此外,在rhG-CSF的应用时机及用药剂量和方法等方面仍存在许多值得探讨的问题。针对以上问题我们进行了两方面的探索。
首先,给予比格犬2.3Gy 90%中子照射以制造中子重度骨髓型ARS动物模型,结果显示照射对照组动物75%死亡,死亡动物平均存活10.8d;照射后出现呕吐、腹泻、血水便等十分严重的胃肠道症状、体温明显升高、全血细胞急剧减少、骨髓造血细胞空虚,从以上情况分析,该照射条件可致中子重度骨髓型ARS。与等效剂量的γ射线照射犬比较,2.3Gy中子照射动物的早期死亡(7d内)发生率增加,死亡时间提前;早期胃肠道症状、感染及临床出血发生时间更早,程度更重;皮肤损伤重;外周血白细胞数下降更为迅速,但白细胞最低值相当。此外,还发现比格犬受到2.3Gy中子照射后,其凝血系统在初期处于高凝状态,极期时处于低凝状态,照射后15d最为明显;凝血功能改变以内源性凝血途径为主,在病程的初期至极期纤维蛋白原含量均明显增高;血小板数量和聚集功能同时下降。照射后早期的高凝状态及毛细血管脆性和通透性增加可能是2.3Gy中子照射动物早期死亡的主要原因之一。
模型制备完成后,一组动物在照射后1h内开始给予rhG-CSF 10μg/kg皮下注射,连续给药21d,结果显示小剂量rhG-CSF连续给药联合对症支持治疗可改善照射动物的生存质量,提高外周血白细胞和中性粒细胞数最低值,有效控制中子照射所致的感染症状,使中子重度骨髓型ARS比格犬全部存活(与照射对照组比较,P<0.05);此外,还发现小剂量rhG-CSF连续给药可纠正2.3Gy中子照射初期的高凝状态,缩短极期时凝血活酶生成时间,加快血凝块形成的速度,改善内源性凝血功能紊乱,下调纤维蛋白原的异常增高,改善血小板聚集功能,从而改善受照射动物初期和极期的凝血功能紊乱,这为ARS早期和极期出血的防治提供了重要线索。
另一组动物在照射后0.5和24h各一次给予rhG-CSF 200μg/kg皮下注射治疗,结果发现大剂量rhG-CSF早期干预联合对症支持治疗同样可提高2.3Gy中子照射比格犬外周血白细胞和中性粒细胞最低值,促进其恢复,使中子重度骨髓型ARS比格犬全部存活(与照射对照组比较,P<0.05);还可减少外周血细胞凋亡,提高2.3Gy中子照射早期外周血有核细胞集落形成能力。此外,还发现大剂量rhG-CSF早期干预不但能减轻免疫器官的损伤,而且还可增强脾脏的免疫功能,表现为脾脏白髓数量明显增加;更重要的是,能够完全有效地促进骨髓造血功能恢复,使骨髓造血细胞的数量和密度保持在正常水平。这提示尽早将骨髓造血细胞动员入外周血可能会减轻造血细胞凋亡和坏死后对骨髓造血微环境的影响,进而有利于骨髓造血功能的恢复。
最后,针对中子辐射损伤效应重的特点,本研究还系统观察了2.3Gy中子照射对比格犬非造血器官的病理组织学及功能改变,2.3Gy中子照射后动物的胃肠损伤主要为功能紊乱,结构损伤较轻。免疫系统的早期改变为细胞数量减少、脾脏和淋巴结萎缩、结构消失、免疫球蛋白生成受抑。rhG-CSF治疗可促进免疫组织的恢复,尤其是大剂量rhG-CSF治疗不但能减轻中子辐射对免疫器官的损伤,而且还可增强脾脏的免疫功能。中子-γ射线混合照射引起的肺部损伤较单纯的γ射线更为严重,但病变过程与γ射线照射基本一致。2.3Gy中子照射所致的生殖系统和肾脏损伤基本上可自行恢复。但引起的大脑皮质内细小血管周围不同程度水肿则难以恢复。2.3Gy中子照射仅在照射后早期引起心肌功能受损,未见明显病理组织学改变。
综上所述,不论是小剂量rhG-CSF连续给药还是大剂量rhG-CSF早期干预均对2.3Gy中子-γ射线混合照射所致重度骨髓型ARS比格犬有明显的治疗作用,可以促进照射犬体内残留造血干/祖细胞的增殖、分化和成熟,从而加速造血功能的重建,表现为中子ARS比格犬极期外周血白细胞和中性粒细胞数最低值的升高,明显降低因白细胞数严重低下而导致的感染并发症的发生率和/或减轻其程度,提高中子ARS比格犬的活存率。
At present, nations which own nuclear weapons still insist on the core thinking of nuclear threaten. Nuclear weapons are deemed as important safeguard to protect nation safety and benefits. Nations which do not own nuclear weapons are actively developing nuclear weapons. Dangers of our country threatened by nuclear weapons from perimeter countries are increasing. In addition, terror activities are outbreak currently. Simple explosion devices maybe used to destroyed nuclear facilities. Besides, in the process of application of nuclear energy and nuclear technology, criticality accidents occurred occasionally due to the operation fault and so on. Either nuclear weapon explosion or great nuclear radiation accidents would result in large crowd received different ratio of mixed fission neutron and gamma ray radiation. Numerous studies demonstrated that the higher the percentage of neutrons, the more severe the biologic response. In order to prepare for nuclear radiation medical emergency, it is important to carry out sdudies on the treatment of high ratio neutron-gamma irradiation evoked acute radiation sickness (ARS).
It is well known that hematopoietic injury is the basic injury of myeloid ARS. At present, recombinant hematopoietic growth factors synthesized through gene engineering recombination technology are the choice drug to promote hematopoietic recovery in ARS treatments. Among the total, recombinant human granulocyte colony-stimulating factor (rhG-CSF) could promote proliferation and differentiation of bone marrow hematopoietic cells into granulocyte colony, induce terminal differentiation of neutrophils and enhance neutrophils’function. RhG-CSF had positive therapeutic effect for gamma ray induced myeloid ARS and received international recognition for its use in ARS treatment. But reports on the treatment of rhG-CSF in severe myeloid ARS induced by high proportion neutron-γray irradiation have rarely been seen yet. Moreover, there were many controversial issues on the usage and dosage of rhG-CSF. We carried out two aspects work to answer the questions above.
First, Beagles were exposed to a unilateral irradiation with a single dose of 2.3Gy 90% neutrons to prepare animal model of neutron severe myeloid ARS. The results showed that 75% animals in the irradiation control group were died. The survival time of decedents was 10.8 days. All of the irradiated dogs showed early signs of gastrointestinal syndromes including loss of appetite, vomiting and diarrhea, one of whom even showed bloody diarrhea. They also exhibited profound cytopenia. Histopathologic evaluation of sternum of died animals showed that there were few hematopoietic cells left in cavitas medullaris accompanying haemorrhage. Analyzed the conditions mentioned above, 2.3Gy neutron unilateral irradiation mainly induced a severe hematopoietic syndrome in this study. Compared with isoeffect dose gamma ray irradiated Beagles, the incidence of early death (within 7 days) in 2.3Gy neutron radiated dogs increased, death time was advanced, the time occurred early gastrointestinal symptom, infection and clinical bleeding was earlier and the degree was more severe, and injuries on skin were more serious. Peripheral blood leucocytes decreased more rapidly, but the nadir of leucocytes under both radiation conditions was equivalent. Moreover, we also found that the blood clotting system was in hypercoagulabale state in the early days after 2.3Gy neutron irradiation, and became hypocoagulabale at acme. Changes of blood clotting function were mainly on intrinsic coagulation pathway. Fibrinogen increased markedly during the course of disease. Platelet counts and aggregation function were decreased at the same time. The main cause of death maybe the hypocoagulabale state and the augmentation of capillary fragility and permeability at the early stage after irradiation.
After the model was prepared, one group of animals was administered 10μg rhG-CSF/kg/d subcutaneously daily from day 0 to day 20 starting within 1 hour post exposure. Results indicated that low dose rhG-CSF administered continuously in combination with supportive care could improve the quality of life of irradiated animals, enhance the nadirs of peripheral blood leucocyte and neutrophil counts, effectively control the infection syndrome, and make irradiated dogs survived eventually (Compared with irradiation control group, P<0.05). Additionally, we also found that low dose rhG-CSF administered daily could also correct hypercoagulabale state induced by 2.3Gy neutron irradiation at the early time post exposure, shorten the thromboplatin generation time, accelerate the formation speed of coagula, improve intrinsic coagulation functional disorder, down regulate the abnormal increase of fibrinogen, and ameliorate platelet aggregation function. Coagulation disorders of irradiated dogs at early time and acme were improved accordingly, which provided an important clue for treatment of hemorrhage at early stage and acme of ARS.
Another group of animals was subcutaneously injected with rhG-CSF at a dose of 200μg/kg early at 0.5 and 24 hours post irradiation. Results showed that twice injection of rhG-CSF early at the first 24 hours in combination with supportive care could also reduce duration of neutropenia, enhance neutrophil nadir and promote neutrophil recovery on the whole, and rescue lethally (2.3Gy neutron) irradiated canines from hematopoietic death (Compared with irradiation control group, P<0.05). Moreover, the apoptosis of peripheral blood cells decreased. The numbers of colony-forming cells (CFU-GM, CFU-E, and BFU-E) in peripheral blood of rhG-CSF treated canines were increased on day 3. In addition, we also found that high dose rhG-CSF early intervention could not only mitigate the injuries of immune organ, but also reinforce the immune function of spleen. What’s more important is that all canines treated with rhG-CSF achieved hematopoietic reconstruction, showing that the quantity and density of myeloid elements were normal in view of pathological section of sternum. The results indicated that rhG-CSF enhanced hematopoietic recovery through mobilizing myeloid elements into peripheral blood early and mitigate the effects of cell apoptosis and necrosis on bone marrow hemopoietic microenvironment.
Finally, in order to observe the non-hematopoietic organ damage induced by 2.3Gy neutron irradiation, pathohistology examination and serum enzymatic methods were used. Results showed that gastrointestinal impairments evoked by 2.3Gy neutron were mainly functional disorder, while structural changes were not apparent. The early changes of immune system were cell population diminished, spleen and lymphoid node atrophied, structure vanished and immunoglobulin production suppressed. Administration of rhG-CSF could promote immune tissues recovery, especially high dose rhG-CSF. Pulmonary impairments induced by mixed fission neutron-gamma irradiation were more severe than that of simple gamma ray, but the pathological changes were basically in accordance with gamma ray. Genital system and kidney damages in 2.3Gy neutron irradiated dogs could recover on their own. However, the dropsy around the minute blood vessel in cerebral cortex was hardly to recover. 2.3Gy neutron irradiation provoked myocardial function impairments at early stage, but did not provoke pathohistology changes.
In conclusion, combination of supportive care and low dose rhG-CSF daily injection or high dose rhG-CSF early intervention was effective in alleviating neutropenia and promoting reconstitution of myelopoiesis, and enhanced survival of 2.3Gy mixed neutron and gamma ray irradiated dogs.
众所周知,造血损伤是骨髓型ARS的基本损伤。目前,利用基因工程重组技术制备的重组造血生长因子已成为促进ARS造血功能恢复治疗中的首选药物。其中重组人粒细胞集落刺激因子(rhG-CSF)具有促进骨髓造血细胞增殖分化形成粒细胞集落、诱导中性粒细胞终末分化和增强中性粒细胞功能等作用,用于γ射线所致骨髓型ARS具有良好的治疗效果,成为国际公认的ARS治疗药物之一。但关于rhG-CSF对中子重度以上骨髓型ARS的治疗效果尚未见文献报道。此外,在rhG-CSF的应用时机及用药剂量和方法等方面仍存在许多值得探讨的问题。针对以上问题我们进行了两方面的探索。
首先,给予比格犬2.3Gy 90%中子照射以制造中子重度骨髓型ARS动物模型,结果显示照射对照组动物75%死亡,死亡动物平均存活10.8d;照射后出现呕吐、腹泻、血水便等十分严重的胃肠道症状、体温明显升高、全血细胞急剧减少、骨髓造血细胞空虚,从以上情况分析,该照射条件可致中子重度骨髓型ARS。与等效剂量的γ射线照射犬比较,2.3Gy中子照射动物的早期死亡(7d内)发生率增加,死亡时间提前;早期胃肠道症状、感染及临床出血发生时间更早,程度更重;皮肤损伤重;外周血白细胞数下降更为迅速,但白细胞最低值相当。此外,还发现比格犬受到2.3Gy中子照射后,其凝血系统在初期处于高凝状态,极期时处于低凝状态,照射后15d最为明显;凝血功能改变以内源性凝血途径为主,在病程的初期至极期纤维蛋白原含量均明显增高;血小板数量和聚集功能同时下降。照射后早期的高凝状态及毛细血管脆性和通透性增加可能是2.3Gy中子照射动物早期死亡的主要原因之一。
模型制备完成后,一组动物在照射后1h内开始给予rhG-CSF 10μg/kg皮下注射,连续给药21d,结果显示小剂量rhG-CSF连续给药联合对症支持治疗可改善照射动物的生存质量,提高外周血白细胞和中性粒细胞数最低值,有效控制中子照射所致的感染症状,使中子重度骨髓型ARS比格犬全部存活(与照射对照组比较,P<0.05);此外,还发现小剂量rhG-CSF连续给药可纠正2.3Gy中子照射初期的高凝状态,缩短极期时凝血活酶生成时间,加快血凝块形成的速度,改善内源性凝血功能紊乱,下调纤维蛋白原的异常增高,改善血小板聚集功能,从而改善受照射动物初期和极期的凝血功能紊乱,这为ARS早期和极期出血的防治提供了重要线索。
另一组动物在照射后0.5和24h各一次给予rhG-CSF 200μg/kg皮下注射治疗,结果发现大剂量rhG-CSF早期干预联合对症支持治疗同样可提高2.3Gy中子照射比格犬外周血白细胞和中性粒细胞最低值,促进其恢复,使中子重度骨髓型ARS比格犬全部存活(与照射对照组比较,P<0.05);还可减少外周血细胞凋亡,提高2.3Gy中子照射早期外周血有核细胞集落形成能力。此外,还发现大剂量rhG-CSF早期干预不但能减轻免疫器官的损伤,而且还可增强脾脏的免疫功能,表现为脾脏白髓数量明显增加;更重要的是,能够完全有效地促进骨髓造血功能恢复,使骨髓造血细胞的数量和密度保持在正常水平。这提示尽早将骨髓造血细胞动员入外周血可能会减轻造血细胞凋亡和坏死后对骨髓造血微环境的影响,进而有利于骨髓造血功能的恢复。
最后,针对中子辐射损伤效应重的特点,本研究还系统观察了2.3Gy中子照射对比格犬非造血器官的病理组织学及功能改变,2.3Gy中子照射后动物的胃肠损伤主要为功能紊乱,结构损伤较轻。免疫系统的早期改变为细胞数量减少、脾脏和淋巴结萎缩、结构消失、免疫球蛋白生成受抑。rhG-CSF治疗可促进免疫组织的恢复,尤其是大剂量rhG-CSF治疗不但能减轻中子辐射对免疫器官的损伤,而且还可增强脾脏的免疫功能。中子-γ射线混合照射引起的肺部损伤较单纯的γ射线更为严重,但病变过程与γ射线照射基本一致。2.3Gy中子照射所致的生殖系统和肾脏损伤基本上可自行恢复。但引起的大脑皮质内细小血管周围不同程度水肿则难以恢复。2.3Gy中子照射仅在照射后早期引起心肌功能受损,未见明显病理组织学改变。
综上所述,不论是小剂量rhG-CSF连续给药还是大剂量rhG-CSF早期干预均对2.3Gy中子-γ射线混合照射所致重度骨髓型ARS比格犬有明显的治疗作用,可以促进照射犬体内残留造血干/祖细胞的增殖、分化和成熟,从而加速造血功能的重建,表现为中子ARS比格犬极期外周血白细胞和中性粒细胞数最低值的升高,明显降低因白细胞数严重低下而导致的感染并发症的发生率和/或减轻其程度,提高中子ARS比格犬的活存率。
At present, nations which own nuclear weapons still insist on the core thinking of nuclear threaten. Nuclear weapons are deemed as important safeguard to protect nation safety and benefits. Nations which do not own nuclear weapons are actively developing nuclear weapons. Dangers of our country threatened by nuclear weapons from perimeter countries are increasing. In addition, terror activities are outbreak currently. Simple explosion devices maybe used to destroyed nuclear facilities. Besides, in the process of application of nuclear energy and nuclear technology, criticality accidents occurred occasionally due to the operation fault and so on. Either nuclear weapon explosion or great nuclear radiation accidents would result in large crowd received different ratio of mixed fission neutron and gamma ray radiation. Numerous studies demonstrated that the higher the percentage of neutrons, the more severe the biologic response. In order to prepare for nuclear radiation medical emergency, it is important to carry out sdudies on the treatment of high ratio neutron-gamma irradiation evoked acute radiation sickness (ARS).
It is well known that hematopoietic injury is the basic injury of myeloid ARS. At present, recombinant hematopoietic growth factors synthesized through gene engineering recombination technology are the choice drug to promote hematopoietic recovery in ARS treatments. Among the total, recombinant human granulocyte colony-stimulating factor (rhG-CSF) could promote proliferation and differentiation of bone marrow hematopoietic cells into granulocyte colony, induce terminal differentiation of neutrophils and enhance neutrophils’function. RhG-CSF had positive therapeutic effect for gamma ray induced myeloid ARS and received international recognition for its use in ARS treatment. But reports on the treatment of rhG-CSF in severe myeloid ARS induced by high proportion neutron-γray irradiation have rarely been seen yet. Moreover, there were many controversial issues on the usage and dosage of rhG-CSF. We carried out two aspects work to answer the questions above.
First, Beagles were exposed to a unilateral irradiation with a single dose of 2.3Gy 90% neutrons to prepare animal model of neutron severe myeloid ARS. The results showed that 75% animals in the irradiation control group were died. The survival time of decedents was 10.8 days. All of the irradiated dogs showed early signs of gastrointestinal syndromes including loss of appetite, vomiting and diarrhea, one of whom even showed bloody diarrhea. They also exhibited profound cytopenia. Histopathologic evaluation of sternum of died animals showed that there were few hematopoietic cells left in cavitas medullaris accompanying haemorrhage. Analyzed the conditions mentioned above, 2.3Gy neutron unilateral irradiation mainly induced a severe hematopoietic syndrome in this study. Compared with isoeffect dose gamma ray irradiated Beagles, the incidence of early death (within 7 days) in 2.3Gy neutron radiated dogs increased, death time was advanced, the time occurred early gastrointestinal symptom, infection and clinical bleeding was earlier and the degree was more severe, and injuries on skin were more serious. Peripheral blood leucocytes decreased more rapidly, but the nadir of leucocytes under both radiation conditions was equivalent. Moreover, we also found that the blood clotting system was in hypercoagulabale state in the early days after 2.3Gy neutron irradiation, and became hypocoagulabale at acme. Changes of blood clotting function were mainly on intrinsic coagulation pathway. Fibrinogen increased markedly during the course of disease. Platelet counts and aggregation function were decreased at the same time. The main cause of death maybe the hypocoagulabale state and the augmentation of capillary fragility and permeability at the early stage after irradiation.
After the model was prepared, one group of animals was administered 10μg rhG-CSF/kg/d subcutaneously daily from day 0 to day 20 starting within 1 hour post exposure. Results indicated that low dose rhG-CSF administered continuously in combination with supportive care could improve the quality of life of irradiated animals, enhance the nadirs of peripheral blood leucocyte and neutrophil counts, effectively control the infection syndrome, and make irradiated dogs survived eventually (Compared with irradiation control group, P<0.05). Additionally, we also found that low dose rhG-CSF administered daily could also correct hypercoagulabale state induced by 2.3Gy neutron irradiation at the early time post exposure, shorten the thromboplatin generation time, accelerate the formation speed of coagula, improve intrinsic coagulation functional disorder, down regulate the abnormal increase of fibrinogen, and ameliorate platelet aggregation function. Coagulation disorders of irradiated dogs at early time and acme were improved accordingly, which provided an important clue for treatment of hemorrhage at early stage and acme of ARS.
Another group of animals was subcutaneously injected with rhG-CSF at a dose of 200μg/kg early at 0.5 and 24 hours post irradiation. Results showed that twice injection of rhG-CSF early at the first 24 hours in combination with supportive care could also reduce duration of neutropenia, enhance neutrophil nadir and promote neutrophil recovery on the whole, and rescue lethally (2.3Gy neutron) irradiated canines from hematopoietic death (Compared with irradiation control group, P<0.05). Moreover, the apoptosis of peripheral blood cells decreased. The numbers of colony-forming cells (CFU-GM, CFU-E, and BFU-E) in peripheral blood of rhG-CSF treated canines were increased on day 3. In addition, we also found that high dose rhG-CSF early intervention could not only mitigate the injuries of immune organ, but also reinforce the immune function of spleen. What’s more important is that all canines treated with rhG-CSF achieved hematopoietic reconstruction, showing that the quantity and density of myeloid elements were normal in view of pathological section of sternum. The results indicated that rhG-CSF enhanced hematopoietic recovery through mobilizing myeloid elements into peripheral blood early and mitigate the effects of cell apoptosis and necrosis on bone marrow hemopoietic microenvironment.
Finally, in order to observe the non-hematopoietic organ damage induced by 2.3Gy neutron irradiation, pathohistology examination and serum enzymatic methods were used. Results showed that gastrointestinal impairments evoked by 2.3Gy neutron were mainly functional disorder, while structural changes were not apparent. The early changes of immune system were cell population diminished, spleen and lymphoid node atrophied, structure vanished and immunoglobulin production suppressed. Administration of rhG-CSF could promote immune tissues recovery, especially high dose rhG-CSF. Pulmonary impairments induced by mixed fission neutron-gamma irradiation were more severe than that of simple gamma ray, but the pathological changes were basically in accordance with gamma ray. Genital system and kidney damages in 2.3Gy neutron irradiated dogs could recover on their own. However, the dropsy around the minute blood vessel in cerebral cortex was hardly to recover. 2.3Gy neutron irradiation provoked myocardial function impairments at early stage, but did not provoke pathohistology changes.
In conclusion, combination of supportive care and low dose rhG-CSF daily injection or high dose rhG-CSF early intervention was effective in alleviating neutropenia and promoting reconstitution of myelopoiesis, and enhanced survival of 2.3Gy mixed neutron and gamma ray irradiated dogs.
引文
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