一氧化碳中毒小鼠脑内Ang-1、Ang-2及Tie-2 mRNA的动态变化及丁苯肽对其影响
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摘要
背景：一氧化碳(Carbon monoxide, CO)是一种无色、无味、无臭、无刺激性的有毒气体,是生活和生产中造成中毒性死亡最常见的窒息性气体。它可以引起机体多个系统损伤,其中大脑损害最为严重,且有一部分急性一氧化碳中毒患者在中毒症状缓解、意识恢复正常后,大约经历2到60天表现正常或基本正常的间歇期后,会再次出现一系列脑病的症状,称为一氧化碳中毒迟发性脑病(Delayed encephalopathy after carbon monoxide poisoning, DEACMP)。其主要表现为记忆受损、意识障碍、锥体外系神经障碍、锥体系神经损害等,是CO中毒最严重的类型。有关急性CO中毒和DEACMP发病机制仍不十分清楚,迄今为止已经提出了许多假说,如缺血缺氧、细胞毒性损伤、再灌注损伤和自由基的形成、兴奋性氨基酸的生成、凋亡机制等。其中缺血缺氧机制在CO中毒脑损伤的发生机理中占有重要地位。近年来,许多研究结果表明,缺血缺氧后,缺血周围区域存在新生血管形成现象,而通过血管新生可以启动损伤区微血管网重建,进而可以改善损伤区微循环组织的血液灌流,这对CO中毒后缺血缺氧神经元的存活具有重要意义。目前,动物实验已证实,脑缺血时脑内可见新生血管形成,而CO中毒后脑血管的分子生理病理变化尚无明确报道。
在新生血管生成过程中,血管生成素(Angiopoiten, Ang)家族发挥着重要作用,它可以特异作用于血管内皮细胞。其中家族中的Ang-1、Ang-2与血管生成密切相关,与内皮细胞表面特异受体Tie-2酪氨酸激酶结合发挥促血管生成作用。Ang/Tie-2系统参与血管新生的最后阶段,通过干预内皮细胞、平滑肌细胞和周细胞的相互作用促进血管生成和重塑,在缺血等病理状态下可作为一种关键的血管生成调节剂。然而CO中毒后脑组织内Ang-1、Ang-2及Tie-2的表达变化无相关报道。
丁苯肽是临床应用于治疗急性脑卒中的一类化学新药,可促进新生血管生成,恢复脑血流的供应,增加缺血区脑血流量和改善脑缺血区微循环,保护线粒体功能,改善全脑缺血后的能量代谢等,涉及脑缺血病理的多个环节,但其对治疗和改善急性CO中毒损伤的分子机制尚不很明确。
目的：本实验拟在建立CO中毒小鼠模型的基础上,从mRNA水平动态观察小鼠海马区Ang-1.Ang-2及Tie-2表达的变化规律,探讨CO中毒对小鼠脑内血管内皮系统的影响,以期能够推测新血管形成机制在脑损伤发生后的作用,并进一步在分子水平研究CO中毒后丁苯肽对血管生成素系统的影响。
实验方法：健康雄性小鼠144只,体重(18-22)g,随机分成空气对照组(48只),染毒(CO)组(48只),丁苯肽组(48只),各组再分为6h、1d、2d、3d、4d、7d、14d、21d、28d,8个亚组。染毒组按照单次腹腔注射法建立CO中毒小鼠模型,空气对照组以等量空气腹腔注射,染毒后丁苯肽组给予丁苯肽(1ml／kg,bid)腹腔注射。相应时间点,处死小鼠,断头取脑,研磨脑组织,提总RNA。采用逆转录-聚合酶链反应(RT-PCR)技术检测各组Ang-1.Ang-2及Tie-2 mRNA水平表达变化。数据以均数±标准差表示,统计学处理采用SPSS 16.0软件进行One-Way ANOVA检验。
结果：
1、CO中毒后,Ang-1.Ang-2和Tie-2 mRNA表达呈双峰性增高。结果显示：与空气对照组相比,CO中毒后,Ang-1.Ang一2和Tie-2 mRNA表达随时间增加(P<0.05),3d后达到第一个高峰(P<0.05),4d后Ang-1.Ang-2和Tie-2 mRNA表达下降,并于7d后,Ang-1、Ang-2和Tie-2 mRNA表达达到第二个高峰(P<0.05),28d后表达水平恢复正常水平。小鼠脑部海马区的Ang／Tie-2系统在CO中毒后表达呈规律性变化。
2、小鼠CO中毒后使用丁苯肽治疗,Ang-1、Ang-2和Tie-2 mRNA表达呈单峰性增高。与CO组相比,使用丁苯肽后,Ang-1、Ang-2和Tie-2mRNA表达未表现双峰性增高,在6h后即出现表达增高(P<0.05),之后逐步增高于3d达到高峰。3d时,丁苯肽组Ang-1 mRNA表达量低于CO组(P<0.05)；Ang-2和Tie-2 mRNA表达量高于CO组(P<0.05)。3d后表达水平逐步下降,于28天恢复正常水平,没有出现CO组的7d高峰。
3、各组问Ang-2／Ang-1比值的变化结果显示,空气对照组Ang-2／Ang-1的比值在6h-28天内保持比较低的水平,比值恒定(0.36±0.03)；CO组的Ang一2／Ang-1比值在6h即升高达到高峰(与空气对照组相比,P<0.05),2d到达低谷,随后比值缓慢上升于7d达到第二个高峰(与空气对照组相比,P<0.05),14天时即恢复正常水平；丁苯肽组的Ang-2／Ang-1比值也在6h即升高达到高峰(与CO组相比,P<0.05),1d～2d时达到低谷,随后比值上升于4d～7d达到高峰(与CO组相比,P<0.05),28天时才恢复正常水平。
结论：
1、CO中毒后小鼠脑部海马区Ang-1、Ang-2和Tie-2在mRNA水平表达呈双峰性增高,第二个高峰可能与DEACMP相关。
2、丁苯肽对CO中毒后的脑保护作用与血管生成素系统相关,可能会通过影响血管生成素系统而预防或治疗DEACMP.
Backgroud:The carbon monoxide (Carbon monoxide, CO) is one kind of a colorless, tasteless, not smelly, the nonirritating toxic gas, which is the most common asphyxiating gas causes toxic death in the life and the production. It may cause organism multi-system damage, that the cerebrum is worst. Especially delayed encenphalopathy after carbon monoxide poisoning (DEACMP) will happen to some people after carbon monoxide poisoning. The clinical manifestation is a group by the acute stupid primarily energetic nerve function disorder, which is the most serious type in CO poisoning. There are many kinds of hypotheses about acute CO poisoning and DEACMP, until now the clear pathogenesis of the disease has not been discovered. These hypotheses include hypoxic-ischemic, cell toxic damage, reperfusion damage and occurrence of free radical, production of excitatory amino acids and apoptosis, and so on. Among the hypotheses, hypoxic-ischemic mechanism plays an important role in exploring the mechanism of brain injury of carbon monoxide poisoning. In recent years, many studies showed the existence of brain injury of neorascularization phenomenon in the surrounding region of ischemia. Vascularization might trigger the rebuilding of capillary vessel net in damage region, and to improve the hemoperfusion of microcirculation tissues. It is important for the survival of the hypoxic-ischenic neurons after CO poisoning. At present, animal experiments already confirmed the existence of brain injury of neorascularization phenomenon in hypoxic-ischemic regions, but it is not reported that Cerebrovascular pathological change after CO poisoning.
During vascularization, angiopoiten (Ang) family plays an important role. In this family, Ang-1 and Ang-2 are closely associated with vascularization, and they can bind recepetor Tie-2 in surface of endothelial cell to enhance vascularization. During the final stage of vascularization, Ang/Tie-2 system play a role to influence the interaction of endothelial cell, smooth muscle cell and pericyte, thereby, to urge the vascularization and vascular remodeling. However, it is not known that dynamic changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain after carbon monoxide poisoning.
Butylphthalide is a kind of new drug used to cure the acute cerebral accident in the clinical. Butylphthalide can enhance angiogenesis, improve cerebral blood supply, ameliorate microcirculation, protect chondriosome, and so on, and is involved with many stages of hypoxic-ischemic mecha-nism. Yet, it is not clear that the mechanism of Butylphthalide curing and improving CO poisoning damages.
Objective:The project is on the basis of carbon monoxide poisoning model of mice, to observe changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain and to approach influence of endothelial system against CO poisoning, and explore effectiveness of vascularization mechanism in brain damage; At the same times, to study protection effect of Butylphthalide curing CO poisoning in molecule level, and to try to provid a rationale and thinking of improving CO poisoning and preventing DEACMP.
Methods:144 healthy Kunming male mice, were divided into Air control group, Carbon monoxide poisoning group and Butylphthalide group, 48 mice in every group. Each group was divided into eight sub-group, as followed:6h, 1d,2d,3d,4d,7d,14d,28d,6 mice in every group. Carbon monoxide poisoning models of mice were established with intraperitoneal injection. We checked the brain tissues of mice in each group according to every time point. Observing changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain by RT-PCR method. All datas were presentated by mean±SD, statistical analysis software of SPSS 16.0 One-Way ANOVA was employed.
Rusult:
1. After carbon monoxide poisoning, Ang-1, Ang-2 and Tie-2 mRNA levels showed an increase with two peaks, respectively in 3 day (7.02±0.11,7.67±0.22 and 8.73±0.07, P＜0.05 comparing with control) and 7 day (6.60±0.36,7.99±0.06 and 7.69±0.05, P＜0.05 comparing with control), the results showed Ang/Tie-2 system quickly reconstruct and restore blood vessel of damage regions.
2. After use of Butylphthalide, Ang-1, Ang-2 and Tie-2 mRNA levels showed an increase with one peak in 3 day (6.04±0.35,8.46±0.11 and 10.66±0.11, comparing with CO group, P< 0.05), moreover, mRNA levels earlier increased than those of CO group. The results showed Butylph-thalide efficaciously protected the mice brain.
3. Results of Ang-2 to Ang-1 showed Ang-2/Ang-1 remained a low level in control group (0.36±0.03), and in CO group, Ang-2/Ang-1 rised a peak in 6h point (comparing with control, P<0.05); In 2d point, Ang-2/Ang-1 got to the lowest level, subsequently, Ang-2/Ang-1 slowly moved and reached another peak (comparing with control, P<0.05), and in 14d point, Ang-2/Ang-1 is normal; in Butylphthalide group, Ang-2/Ang-1 also rised a peak in 6h point (comparing with CO group, P< 0.05); In 1d-2d point, Ang-2/Ang-1 got to the lowest level, subsequently, Ang-2/Ang-l slowly moved and reached another peak in 4d-7d (comparing with CO group, P< 0.05), and in 28d point, Ang-2/Ang-1 is normal.
Conclusion:
1. After carbon monoxide poisoning, Ang-1, Ang-2 and Tie-2 mRNA levels in the brain showed an increase with two peaks, and it suggested that DEACMP might happen. Ang/Tie-2 system in cerebrovascular endothelial cell showed up the regular changes, and played an important role to reconstruct and restore vessels.
2. Butylphthalide could enhance angiogenesis, improve cerebral blood supply and ameliorate microcirculation, so Butylphthalide might cure and improve CO poisoning damages and prevent DEACMP.
在新生血管生成过程中,血管生成素(Angiopoiten, Ang)家族发挥着重要作用,它可以特异作用于血管内皮细胞。其中家族中的Ang-1、Ang-2与血管生成密切相关,与内皮细胞表面特异受体Tie-2酪氨酸激酶结合发挥促血管生成作用。Ang/Tie-2系统参与血管新生的最后阶段,通过干预内皮细胞、平滑肌细胞和周细胞的相互作用促进血管生成和重塑,在缺血等病理状态下可作为一种关键的血管生成调节剂。然而CO中毒后脑组织内Ang-1、Ang-2及Tie-2的表达变化无相关报道。
丁苯肽是临床应用于治疗急性脑卒中的一类化学新药,可促进新生血管生成,恢复脑血流的供应,增加缺血区脑血流量和改善脑缺血区微循环,保护线粒体功能,改善全脑缺血后的能量代谢等,涉及脑缺血病理的多个环节,但其对治疗和改善急性CO中毒损伤的分子机制尚不很明确。
目的：本实验拟在建立CO中毒小鼠模型的基础上,从mRNA水平动态观察小鼠海马区Ang-1.Ang-2及Tie-2表达的变化规律,探讨CO中毒对小鼠脑内血管内皮系统的影响,以期能够推测新血管形成机制在脑损伤发生后的作用,并进一步在分子水平研究CO中毒后丁苯肽对血管生成素系统的影响。
实验方法：健康雄性小鼠144只,体重(18-22)g,随机分成空气对照组(48只),染毒(CO)组(48只),丁苯肽组(48只),各组再分为6h、1d、2d、3d、4d、7d、14d、21d、28d,8个亚组。染毒组按照单次腹腔注射法建立CO中毒小鼠模型,空气对照组以等量空气腹腔注射,染毒后丁苯肽组给予丁苯肽(1ml／kg,bid)腹腔注射。相应时间点,处死小鼠,断头取脑,研磨脑组织,提总RNA。采用逆转录-聚合酶链反应(RT-PCR)技术检测各组Ang-1.Ang-2及Tie-2 mRNA水平表达变化。数据以均数±标准差表示,统计学处理采用SPSS 16.0软件进行One-Way ANOVA检验。
结果：
1、CO中毒后,Ang-1.Ang-2和Tie-2 mRNA表达呈双峰性增高。结果显示：与空气对照组相比,CO中毒后,Ang-1.Ang一2和Tie-2 mRNA表达随时间增加(P<0.05),3d后达到第一个高峰(P<0.05),4d后Ang-1.Ang-2和Tie-2 mRNA表达下降,并于7d后,Ang-1、Ang-2和Tie-2 mRNA表达达到第二个高峰(P<0.05),28d后表达水平恢复正常水平。小鼠脑部海马区的Ang／Tie-2系统在CO中毒后表达呈规律性变化。
2、小鼠CO中毒后使用丁苯肽治疗,Ang-1、Ang-2和Tie-2 mRNA表达呈单峰性增高。与CO组相比,使用丁苯肽后,Ang-1、Ang-2和Tie-2mRNA表达未表现双峰性增高,在6h后即出现表达增高(P<0.05),之后逐步增高于3d达到高峰。3d时,丁苯肽组Ang-1 mRNA表达量低于CO组(P<0.05)；Ang-2和Tie-2 mRNA表达量高于CO组(P<0.05)。3d后表达水平逐步下降,于28天恢复正常水平,没有出现CO组的7d高峰。
3、各组问Ang-2／Ang-1比值的变化结果显示,空气对照组Ang-2／Ang-1的比值在6h-28天内保持比较低的水平,比值恒定(0.36±0.03)；CO组的Ang一2／Ang-1比值在6h即升高达到高峰(与空气对照组相比,P<0.05),2d到达低谷,随后比值缓慢上升于7d达到第二个高峰(与空气对照组相比,P<0.05),14天时即恢复正常水平；丁苯肽组的Ang-2／Ang-1比值也在6h即升高达到高峰(与CO组相比,P<0.05),1d～2d时达到低谷,随后比值上升于4d～7d达到高峰(与CO组相比,P<0.05),28天时才恢复正常水平。
结论：
1、CO中毒后小鼠脑部海马区Ang-1、Ang-2和Tie-2在mRNA水平表达呈双峰性增高,第二个高峰可能与DEACMP相关。
2、丁苯肽对CO中毒后的脑保护作用与血管生成素系统相关,可能会通过影响血管生成素系统而预防或治疗DEACMP.
Backgroud:The carbon monoxide (Carbon monoxide, CO) is one kind of a colorless, tasteless, not smelly, the nonirritating toxic gas, which is the most common asphyxiating gas causes toxic death in the life and the production. It may cause organism multi-system damage, that the cerebrum is worst. Especially delayed encenphalopathy after carbon monoxide poisoning (DEACMP) will happen to some people after carbon monoxide poisoning. The clinical manifestation is a group by the acute stupid primarily energetic nerve function disorder, which is the most serious type in CO poisoning. There are many kinds of hypotheses about acute CO poisoning and DEACMP, until now the clear pathogenesis of the disease has not been discovered. These hypotheses include hypoxic-ischemic, cell toxic damage, reperfusion damage and occurrence of free radical, production of excitatory amino acids and apoptosis, and so on. Among the hypotheses, hypoxic-ischemic mechanism plays an important role in exploring the mechanism of brain injury of carbon monoxide poisoning. In recent years, many studies showed the existence of brain injury of neorascularization phenomenon in the surrounding region of ischemia. Vascularization might trigger the rebuilding of capillary vessel net in damage region, and to improve the hemoperfusion of microcirculation tissues. It is important for the survival of the hypoxic-ischenic neurons after CO poisoning. At present, animal experiments already confirmed the existence of brain injury of neorascularization phenomenon in hypoxic-ischemic regions, but it is not reported that Cerebrovascular pathological change after CO poisoning.
During vascularization, angiopoiten (Ang) family plays an important role. In this family, Ang-1 and Ang-2 are closely associated with vascularization, and they can bind recepetor Tie-2 in surface of endothelial cell to enhance vascularization. During the final stage of vascularization, Ang/Tie-2 system play a role to influence the interaction of endothelial cell, smooth muscle cell and pericyte, thereby, to urge the vascularization and vascular remodeling. However, it is not known that dynamic changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain after carbon monoxide poisoning.
Butylphthalide is a kind of new drug used to cure the acute cerebral accident in the clinical. Butylphthalide can enhance angiogenesis, improve cerebral blood supply, ameliorate microcirculation, protect chondriosome, and so on, and is involved with many stages of hypoxic-ischemic mecha-nism. Yet, it is not clear that the mechanism of Butylphthalide curing and improving CO poisoning damages.
Objective:The project is on the basis of carbon monoxide poisoning model of mice, to observe changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain and to approach influence of endothelial system against CO poisoning, and explore effectiveness of vascularization mechanism in brain damage; At the same times, to study protection effect of Butylphthalide curing CO poisoning in molecule level, and to try to provid a rationale and thinking of improving CO poisoning and preventing DEACMP.
Methods:144 healthy Kunming male mice, were divided into Air control group, Carbon monoxide poisoning group and Butylphthalide group, 48 mice in every group. Each group was divided into eight sub-group, as followed:6h, 1d,2d,3d,4d,7d,14d,28d,6 mice in every group. Carbon monoxide poisoning models of mice were established with intraperitoneal injection. We checked the brain tissues of mice in each group according to every time point. Observing changes of Ang-1, Ang-2 and Tie-2 mRNA levels in mice brain by RT-PCR method. All datas were presentated by mean±SD, statistical analysis software of SPSS 16.0 One-Way ANOVA was employed.
Rusult:
1. After carbon monoxide poisoning, Ang-1, Ang-2 and Tie-2 mRNA levels showed an increase with two peaks, respectively in 3 day (7.02±0.11,7.67±0.22 and 8.73±0.07, P＜0.05 comparing with control) and 7 day (6.60±0.36,7.99±0.06 and 7.69±0.05, P＜0.05 comparing with control), the results showed Ang/Tie-2 system quickly reconstruct and restore blood vessel of damage regions.
2. After use of Butylphthalide, Ang-1, Ang-2 and Tie-2 mRNA levels showed an increase with one peak in 3 day (6.04±0.35,8.46±0.11 and 10.66±0.11, comparing with CO group, P< 0.05), moreover, mRNA levels earlier increased than those of CO group. The results showed Butylph-thalide efficaciously protected the mice brain.
3. Results of Ang-2 to Ang-1 showed Ang-2/Ang-1 remained a low level in control group (0.36±0.03), and in CO group, Ang-2/Ang-1 rised a peak in 6h point (comparing with control, P<0.05); In 2d point, Ang-2/Ang-1 got to the lowest level, subsequently, Ang-2/Ang-1 slowly moved and reached another peak (comparing with control, P<0.05), and in 14d point, Ang-2/Ang-1 is normal; in Butylphthalide group, Ang-2/Ang-1 also rised a peak in 6h point (comparing with CO group, P< 0.05); In 1d-2d point, Ang-2/Ang-1 got to the lowest level, subsequently, Ang-2/Ang-l slowly moved and reached another peak in 4d-7d (comparing with CO group, P< 0.05), and in 28d point, Ang-2/Ang-1 is normal.
Conclusion:
1. After carbon monoxide poisoning, Ang-1, Ang-2 and Tie-2 mRNA levels in the brain showed an increase with two peaks, and it suggested that DEACMP might happen. Ang/Tie-2 system in cerebrovascular endothelial cell showed up the regular changes, and played an important role to reconstruct and restore vessels.
2. Butylphthalide could enhance angiogenesis, improve cerebral blood supply and ameliorate microcirculation, so Butylphthalide might cure and improve CO poisoning damages and prevent DEACMP.
引文
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