脊髓爆震伤后神经细胞的形态学变化及药物干预治疗的初步研究
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摘要
随着世界军事科学技术的变革和战略战术理论的转变,具有多因素、多途径、多处杀伤效应的爆炸性武器在现代战争中应用越来越广。这就使得爆震伤在现代战争中所占的比重越来越大。在最近的几场局部战争中,新型导弹和新型炸药导致的各种爆震性损伤层出不穷;在平时的恐怖主义活动和案件事故当中,这类损伤的发生率和致死率也是居高不下。因此,爆震性损伤已经成为各个医学学科研究的重点和热点。在战时脊髓损伤当中,脊髓爆震伤的发生率也越来越高,而且已经成为野战外科领域研究的热点和迫切需要解决的问题。通过研究脊髓爆震伤的损伤机制和救治方案,将为这类损伤的预防与诊治提供重要的理论依据和实践指导。
因此,本课题的主要目的是研究在现代战争条件下脊髓爆震伤后,脊髓的病理变化、细胞损伤机制,以及在野战条件下进行早期救治的最佳方案,为提高我军战斗力,降低伤残率服务。
目的:观察不同爆炸距离下脊髓爆震伤(冲击波损伤)动物实验模型的大体病理学改变,分析脊髓爆震伤的早期伤情变化及致伤因素;观察脊髓爆震伤后神经细胞的形态学变化,检测二次损伤中凋亡现象是否在存在,并记录凋亡细胞的时空分布特点;研究大剂量维生素C(Vit C)+β-七叶皂甙钠(SA)联合治疗脊髓爆震伤的疗效,并与目前的常规治疗方法进行对比,探索它们的应用前景。
方法:(1)15只家兔在背部损伤区备皮,麻醉后选择1cm、2 cm、3cm、3.5cm、4cm(n=3)五个爆炸距离,电控引爆,观察动物全身及脊髓的大体病理学损伤情况,分析致伤因素以及早期损伤的变化情况;(2)在4cm的爆震距离下,将96只家兔随机分为空白对照组(n=16)和实验组(n=80)。其中空白对照组未爆震损伤。实验组电控引爆后,有4只动物被排除出实验组。在剩余的动物中,36只动物分别于损伤后8h(n=6)、1d(n=6)、3d(n=6)、7d(n=6)、14d(n=6)和30d(n=6)取材,用于HE染色和TUNEL染色;20只动物则分别于损伤后8h(n=5)、1d(n=5)、3d(n=5)和7d(n=5)取材,用于透射电镜检测;20只动物则分别于损伤后8h(n=5)、1d(n=5)、3d(n=5)和7d(n=5)取材,用于DNA电泳分析。各组取材之前均运用Tarlov’s评分评估下肢的运动功能;(3)在36只家兔中,除空白对照组(A组,n=6)未爆炸损伤外,其余家兔均在爆炸距离距为4cm的情况下,电击引爆。然后将其随机分到损伤对照组(B组,n=6)、地塞米松治疗组(C组,n=6)、VitC治疗组(D组,n=6)、SA治疗组(E组,n=6)和VitC+SA治疗组(F组,n=6)共5组。各组均运用Tarlov’s评分法评估动物8h、1d、3d、7d和14d时的下肢运动功能,而且于损伤后14天统一取材,并应用HE染色和TUNEL染色技术,检测药物对爆震损伤后脊髓的治疗情况。
结果:(1)随着爆炸距离的延长,脊髓爆震伤后动物的伤情明显减轻。而且动物的个体差异对相同距离下脊髓爆震伤后的伤情也有比较明显的影响。爆炸冲击波是脊髓爆震伤的主要致伤因素。其导致的肺脏等空腔脏器的严重损伤也是动物死亡的主要原因。因此,在治疗脊髓爆震伤的同时必须注重对肺脏等其他重要脏器的治疗;(2)对脊髓组织采用HE染色和TUNEL技术等方法观察细胞的凋亡状况,证实脊髓爆震伤后广泛存在神经细胞凋亡,而且发现爆震伤后神经细胞的凋亡时空分布具有以下特征:①损伤后在灰质和白质中均检测到阳性细胞,但是灰质中的凋亡细胞特别少,而且多数为胶质细胞,凋亡的神经元细胞很少见,可能神经元多数都是以坏死的形式死亡的;②胶质细胞在伤后很长时期内陆续通过凋亡的方式死亡,而神经元的死亡则主要是以坏死为主,而且发生的时间较早;③灰质中的凋亡细胞在1d时达到高峰,但是同时期白质中的凋亡细胞数目比灰质中要多的多。而白质中的凋亡细胞数目则在7d时达高峰,主要分布在白质的周边,以胶质细胞为主。随后凋亡细胞数明显下降,但到14d时仍可见部分凋亡细胞;④相邻脊髓节段的阳性细胞表达在7d时明显比爆心节段多,而且爆震伤后凋亡的波及范围从上到下可达约4cm之多;(3)实验证实脊髓爆震伤后早期单独使用SA治疗,可以有效的提高下肢运动功能的恢复、保存前角运动神经元的数目和降低凋亡细胞的数量,而且与激素治疗组相比并没有统计学差异;单独大剂量Vit C治疗除可有效保护前角运动神经元外,并不能提高下肢的运动恢复和减少凋亡细胞的数目;而联合使用大剂量Vit C+SA治疗效果较佳,与单独应用大剂量Vit C、SA或激素治疗相比均有统计学差异。
结论:(1)建立开放式液体环境下脊髓爆震伤模型也许对研究爆炸冲击波对脊髓的损伤机制会有更大的帮助;(2)本实验发现:脊髓爆震伤后同样存在神经细胞的凋亡现象,但是凋亡细胞主要为胶质细胞,而且有其时相和空间分布特点;(3)兔脊髓爆震伤后早期使用大剂量Vit C+β-七叶皂甙钠(SA)具有治疗作用,而且效果优于单独应用大剂量维生素C(Vit C)、SA或激素。
With the changes of military science and transition of strategies and tactics theory, the incidence of blast injuries in the modern battlefield has increased rapidly due to the abusage of modern explosive weapons. In the recent local wars, the injuries, which were caused by the new missiles and new explosive, were more and more widely. In the terrorist activities and incidents, the incidence of such injuries was also high. So the blast injury has become the focus of various medical areas. In battle injuries of spine, the incidence of the blast injury of spinal cord became more and more highly. It was studying the mechanisms and treatment of the blast injury of spinal cord that provide an important theoretical basis and practical guidance for the diagnosis and treatment of such injury.
Therefore, the main purpose of the present research was to study the pathos-mechanism of the blast injury of spinal cord, and found the preferred early treatment in order to enhance our fighting strength of military and reduce the disability rate.
Objective: (1) To investigate the macro-pathological changes of animals, which were injured at different distance between the explosives and animals, and analyze the early traumatic condition and risk factor of the blast injury to spinal cord; (2) To study morphological changes of the neural cells and the characteristics of temporal and spatial distribution of apoptotic neural cells after the blast injury of spinal cord; (3) Compared with the current conventional treatment for SCI, to investigate the effects of therapy with high-dose Vitamin C combined with sodiumβ-aescinate in spinal cord blast injury.
Method: (1) Fifteen rabbits were shaved in the dorsal surface of T9-T10 level and were fixed respectively on the special plate with prone position. Then animals were injured in 1cm, 2cm, 3cm, 3.5cm or 4cm distance under the explosives (n=3). By postmortem examination, to observe the macro-pathological changes of animals and the gross pathology of the spinal cord; (2) The formal experiments were performed on 96 adult male rabbits. And these animals were randomly divided into two groups: sham group (n=16) and experimental group (n=80). After detonation, four rabbits were dead and excluded from the experimental group. So other thirty-six rabbits were anesthetized and perfused with 4% paraformaldehyde for HE and TUNEL staining at 8 hours, 1, 3, 7, 14 or 30 days after explosive detonation (n=6 at each time point). In addition, twenty animals were perfused for TEM at 8 hours, 1, 3 or 7 days after explosive detonation (n=5 at each time point). For DNA analysis, another twenty animals were killed at 8 hours, 1, 3 or 7 days after explosive detonation (n=5 at each time point). All animal’s neurological deficit caused by the SCI was assessed by using a modified Tarlov’s scale at 8 hours, 1, 3, 7, 14 or 30 days after SCI; (3) Thirty-six rabbits were randomly divided into sham group (Group A,n=6), control group(Group B,n=6), dexamethasone group (Group C), VitC group (Group D,n=6), SA group(Group E,n=6) and VitC+SA group(Group F,n=6). All experimental groups were made explosive wound by 0.7g cyclotrimethylene trinitramine, and the change of neural function was observed by Tarlov’s scale. The injured spinal cords were taken for morphological studies at 14d, including HE staining and the TUNEL method.
Result: (1) With the extension of distance between the explosives and animals, the grade of the blast injury of spinal cord was significantly reduced. And the individual differences of animals were an obvious factor to the traumatic condition of blast injury to the spinal cord in the model. The blast wave was the main factor to the blast injury of spinal cord injury and the severe lung or other hollow organs injury. However the hollow organs injury was the main reason of animal death. Therefore, the treatment of hollow organs such as lung was very important in the blast injury of spinal cord; (2) In the present study, neuronal apoptosis was confirmed in the blast injury of spinal cord by HE staining and TUNEL methods. However the characteristics of temporal and spatial distribution of apoptotic neural cells after the blast injury of spinal cord were very special.①: The apoptotic cells were found in both the gray matter and white matter. But the apoptotic cells in the gray matter were extremely rare, and most TUNEL positive cells were glial cells. The majority of neurons were probably dead in the form of necrosis.②: The apoptosis of glial cells existed in a very long period after injury. However the death of neurons was mainly necrosis at earlier time.③: The value of apoptotic cells in gray matter was maximal at the 1st day after injury. But most TUNEL positive cells were glial cells in white matter at the same time. The value of apoptotic cells in white matter was maximal at the 7th day after injury and decreased subsequently. But the apoptotic cells still exist at 14th day after detonation.④: Lengthways, the value of positive cells in adjacent spinal cord was more than the value of the centric spinal cord at 7th day after detonation. And the affected area of spinal cord was up to about 4cm. (3) In the present research, motor function was significantly improved in SA group. In SA-treated rabbits, both necrosis and apoptosis decreased and more motoneurons survived. So the SA had neuroprotective effects on the blast injury of the spinal cord in rabbits. However there was no significant difference between hormone therapy and SA therapy. A large dose of Vit C therapy had effective protection to the motor neurons in anterior horn, but could not improve the recovery of motor function and reduce the number of apoptotic cells. Early high-dose Vit C combined with SA was superior to high-dose VitC, SA or hormone therapy.
Conclusions: (1) The establishment of an animal model of explosive blast injury to the spinal cord, which the spinal cord was injured with controlled impact in liquid environment after laminectomy, may be useful in the study of the mechanism of the blast injury to spinal cord. (2) Neuronal apoptosis absolutely existed in the blast injury of spinal cord. But apoptotic cells mainly were glial cells and the apoptotic characteristics was particularly. (3) Early high-dose Vit C combined with SA was capable of treating the spinal cord blast injury, and was superior to high-dose Vit C, SA or hormone therapy.
因此,本课题的主要目的是研究在现代战争条件下脊髓爆震伤后,脊髓的病理变化、细胞损伤机制,以及在野战条件下进行早期救治的最佳方案,为提高我军战斗力,降低伤残率服务。
目的:观察不同爆炸距离下脊髓爆震伤(冲击波损伤)动物实验模型的大体病理学改变,分析脊髓爆震伤的早期伤情变化及致伤因素;观察脊髓爆震伤后神经细胞的形态学变化,检测二次损伤中凋亡现象是否在存在,并记录凋亡细胞的时空分布特点;研究大剂量维生素C(Vit C)+β-七叶皂甙钠(SA)联合治疗脊髓爆震伤的疗效,并与目前的常规治疗方法进行对比,探索它们的应用前景。
方法:(1)15只家兔在背部损伤区备皮,麻醉后选择1cm、2 cm、3cm、3.5cm、4cm(n=3)五个爆炸距离,电控引爆,观察动物全身及脊髓的大体病理学损伤情况,分析致伤因素以及早期损伤的变化情况;(2)在4cm的爆震距离下,将96只家兔随机分为空白对照组(n=16)和实验组(n=80)。其中空白对照组未爆震损伤。实验组电控引爆后,有4只动物被排除出实验组。在剩余的动物中,36只动物分别于损伤后8h(n=6)、1d(n=6)、3d(n=6)、7d(n=6)、14d(n=6)和30d(n=6)取材,用于HE染色和TUNEL染色;20只动物则分别于损伤后8h(n=5)、1d(n=5)、3d(n=5)和7d(n=5)取材,用于透射电镜检测;20只动物则分别于损伤后8h(n=5)、1d(n=5)、3d(n=5)和7d(n=5)取材,用于DNA电泳分析。各组取材之前均运用Tarlov’s评分评估下肢的运动功能;(3)在36只家兔中,除空白对照组(A组,n=6)未爆炸损伤外,其余家兔均在爆炸距离距为4cm的情况下,电击引爆。然后将其随机分到损伤对照组(B组,n=6)、地塞米松治疗组(C组,n=6)、VitC治疗组(D组,n=6)、SA治疗组(E组,n=6)和VitC+SA治疗组(F组,n=6)共5组。各组均运用Tarlov’s评分法评估动物8h、1d、3d、7d和14d时的下肢运动功能,而且于损伤后14天统一取材,并应用HE染色和TUNEL染色技术,检测药物对爆震损伤后脊髓的治疗情况。
结果:(1)随着爆炸距离的延长,脊髓爆震伤后动物的伤情明显减轻。而且动物的个体差异对相同距离下脊髓爆震伤后的伤情也有比较明显的影响。爆炸冲击波是脊髓爆震伤的主要致伤因素。其导致的肺脏等空腔脏器的严重损伤也是动物死亡的主要原因。因此,在治疗脊髓爆震伤的同时必须注重对肺脏等其他重要脏器的治疗;(2)对脊髓组织采用HE染色和TUNEL技术等方法观察细胞的凋亡状况,证实脊髓爆震伤后广泛存在神经细胞凋亡,而且发现爆震伤后神经细胞的凋亡时空分布具有以下特征:①损伤后在灰质和白质中均检测到阳性细胞,但是灰质中的凋亡细胞特别少,而且多数为胶质细胞,凋亡的神经元细胞很少见,可能神经元多数都是以坏死的形式死亡的;②胶质细胞在伤后很长时期内陆续通过凋亡的方式死亡,而神经元的死亡则主要是以坏死为主,而且发生的时间较早;③灰质中的凋亡细胞在1d时达到高峰,但是同时期白质中的凋亡细胞数目比灰质中要多的多。而白质中的凋亡细胞数目则在7d时达高峰,主要分布在白质的周边,以胶质细胞为主。随后凋亡细胞数明显下降,但到14d时仍可见部分凋亡细胞;④相邻脊髓节段的阳性细胞表达在7d时明显比爆心节段多,而且爆震伤后凋亡的波及范围从上到下可达约4cm之多;(3)实验证实脊髓爆震伤后早期单独使用SA治疗,可以有效的提高下肢运动功能的恢复、保存前角运动神经元的数目和降低凋亡细胞的数量,而且与激素治疗组相比并没有统计学差异;单独大剂量Vit C治疗除可有效保护前角运动神经元外,并不能提高下肢的运动恢复和减少凋亡细胞的数目;而联合使用大剂量Vit C+SA治疗效果较佳,与单独应用大剂量Vit C、SA或激素治疗相比均有统计学差异。
结论:(1)建立开放式液体环境下脊髓爆震伤模型也许对研究爆炸冲击波对脊髓的损伤机制会有更大的帮助;(2)本实验发现:脊髓爆震伤后同样存在神经细胞的凋亡现象,但是凋亡细胞主要为胶质细胞,而且有其时相和空间分布特点;(3)兔脊髓爆震伤后早期使用大剂量Vit C+β-七叶皂甙钠(SA)具有治疗作用,而且效果优于单独应用大剂量维生素C(Vit C)、SA或激素。
With the changes of military science and transition of strategies and tactics theory, the incidence of blast injuries in the modern battlefield has increased rapidly due to the abusage of modern explosive weapons. In the recent local wars, the injuries, which were caused by the new missiles and new explosive, were more and more widely. In the terrorist activities and incidents, the incidence of such injuries was also high. So the blast injury has become the focus of various medical areas. In battle injuries of spine, the incidence of the blast injury of spinal cord became more and more highly. It was studying the mechanisms and treatment of the blast injury of spinal cord that provide an important theoretical basis and practical guidance for the diagnosis and treatment of such injury.
Therefore, the main purpose of the present research was to study the pathos-mechanism of the blast injury of spinal cord, and found the preferred early treatment in order to enhance our fighting strength of military and reduce the disability rate.
Objective: (1) To investigate the macro-pathological changes of animals, which were injured at different distance between the explosives and animals, and analyze the early traumatic condition and risk factor of the blast injury to spinal cord; (2) To study morphological changes of the neural cells and the characteristics of temporal and spatial distribution of apoptotic neural cells after the blast injury of spinal cord; (3) Compared with the current conventional treatment for SCI, to investigate the effects of therapy with high-dose Vitamin C combined with sodiumβ-aescinate in spinal cord blast injury.
Method: (1) Fifteen rabbits were shaved in the dorsal surface of T9-T10 level and were fixed respectively on the special plate with prone position. Then animals were injured in 1cm, 2cm, 3cm, 3.5cm or 4cm distance under the explosives (n=3). By postmortem examination, to observe the macro-pathological changes of animals and the gross pathology of the spinal cord; (2) The formal experiments were performed on 96 adult male rabbits. And these animals were randomly divided into two groups: sham group (n=16) and experimental group (n=80). After detonation, four rabbits were dead and excluded from the experimental group. So other thirty-six rabbits were anesthetized and perfused with 4% paraformaldehyde for HE and TUNEL staining at 8 hours, 1, 3, 7, 14 or 30 days after explosive detonation (n=6 at each time point). In addition, twenty animals were perfused for TEM at 8 hours, 1, 3 or 7 days after explosive detonation (n=5 at each time point). For DNA analysis, another twenty animals were killed at 8 hours, 1, 3 or 7 days after explosive detonation (n=5 at each time point). All animal’s neurological deficit caused by the SCI was assessed by using a modified Tarlov’s scale at 8 hours, 1, 3, 7, 14 or 30 days after SCI; (3) Thirty-six rabbits were randomly divided into sham group (Group A,n=6), control group(Group B,n=6), dexamethasone group (Group C), VitC group (Group D,n=6), SA group(Group E,n=6) and VitC+SA group(Group F,n=6). All experimental groups were made explosive wound by 0.7g cyclotrimethylene trinitramine, and the change of neural function was observed by Tarlov’s scale. The injured spinal cords were taken for morphological studies at 14d, including HE staining and the TUNEL method.
Result: (1) With the extension of distance between the explosives and animals, the grade of the blast injury of spinal cord was significantly reduced. And the individual differences of animals were an obvious factor to the traumatic condition of blast injury to the spinal cord in the model. The blast wave was the main factor to the blast injury of spinal cord injury and the severe lung or other hollow organs injury. However the hollow organs injury was the main reason of animal death. Therefore, the treatment of hollow organs such as lung was very important in the blast injury of spinal cord; (2) In the present study, neuronal apoptosis was confirmed in the blast injury of spinal cord by HE staining and TUNEL methods. However the characteristics of temporal and spatial distribution of apoptotic neural cells after the blast injury of spinal cord were very special.①: The apoptotic cells were found in both the gray matter and white matter. But the apoptotic cells in the gray matter were extremely rare, and most TUNEL positive cells were glial cells. The majority of neurons were probably dead in the form of necrosis.②: The apoptosis of glial cells existed in a very long period after injury. However the death of neurons was mainly necrosis at earlier time.③: The value of apoptotic cells in gray matter was maximal at the 1st day after injury. But most TUNEL positive cells were glial cells in white matter at the same time. The value of apoptotic cells in white matter was maximal at the 7th day after injury and decreased subsequently. But the apoptotic cells still exist at 14th day after detonation.④: Lengthways, the value of positive cells in adjacent spinal cord was more than the value of the centric spinal cord at 7th day after detonation. And the affected area of spinal cord was up to about 4cm. (3) In the present research, motor function was significantly improved in SA group. In SA-treated rabbits, both necrosis and apoptosis decreased and more motoneurons survived. So the SA had neuroprotective effects on the blast injury of the spinal cord in rabbits. However there was no significant difference between hormone therapy and SA therapy. A large dose of Vit C therapy had effective protection to the motor neurons in anterior horn, but could not improve the recovery of motor function and reduce the number of apoptotic cells. Early high-dose Vit C combined with SA was superior to high-dose VitC, SA or hormone therapy.
Conclusions: (1) The establishment of an animal model of explosive blast injury to the spinal cord, which the spinal cord was injured with controlled impact in liquid environment after laminectomy, may be useful in the study of the mechanism of the blast injury to spinal cord. (2) Neuronal apoptosis absolutely existed in the blast injury of spinal cord. But apoptotic cells mainly were glial cells and the apoptotic characteristics was particularly. (3) Early high-dose Vit C combined with SA was capable of treating the spinal cord blast injury, and was superior to high-dose Vit C, SA or hormone therapy.
引文
1.朱胜修,李主一.实用四肢脊柱战伤治疗手册[M] .北京:人民军医出版社,2000. 355
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