C3基因敲除抑制炎症反应促进小鼠脊髓损伤后再生与功能恢复的实验研究
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摘要
脊髓损伤(spinal cord injury, SCI)以其高致残率和死亡率而倍受关注。SCI的最终神经学损害由两种机制引起,即原发性损伤和继发性损伤。前者包括机械压迫、出血、电解质从受损细胞中外溢等;后者包括水肿、炎症反应、局部缺血、生长因子、细胞因子、再灌注、Ca2+溢出以及过氧化基团异常变化等对脊髓产生的损害作用。近年来对SCI的研究主要集中在损伤后期组织再生方面,如神经干细胞移植或嗅鞘细胞移植等,但收效甚微。主要原因就是忽略了继发性损伤带来的严重影响,损伤早期残存的神经元没有得到及时的保护,从而导致后期再生的先决条件欠缺。对于SCI来说,原发性损伤是一个不可逆转的过程,而继发性损伤则是一个可逆且可控的过程。因此,在减低原发性损伤因素的同时,应用多种手段,如减轻炎症免疫反应、阻断神经毒性损伤、减少凋亡发生等,尽可能把继发性损伤的程度降到最低,已成为SCI早期治疗的研究热点。
在继发性损伤早期,存在一个重要的炎症反应过程,它能触发其后发生的一系列针对受损部位细胞和分子水平的反应;此外,炎症反应可以导致受损局部胶质瘢痕的形成,从而进一步阻碍再生。抑制炎症反应能够促进中枢神经系统(central nervous system, CNS)的再生与功能恢复。值得注意的是,炎症过程引起了补体系统的激活,激活的补体片段又能通过多种途径导致炎症反应,对自身组织成分造成损害,加重SCI后的继发性损伤。那么是否可以通过阻断补体系统的激活来抑制炎症反应,从而减轻SCI后的继发性损伤呢?通过何种方式才能阻断补体系统的激活呢?我们选择敲除补体C3基因。因为已知补体系统的三条激活途径——包括经典途径、凝集素途径和旁路途径,虽然启动途径不同,但最后都汇集于一点,即C3转化酶对C3的分解,并在分解之后的活化过程中产生许多具有炎症介质作用的活性片断,如C3a、C4a和C5a等,最后进入共同的末端通路,形成攻膜复合体(membrane attack complx,MAC),并导致炎症反应。可见C3在补体系统已知的三条激活途径中处于枢纽地位,是补体系统激活的必要条件。本研究的目的就是通过敲除补体C3基因来抑制炎症反应,从而减轻继发性损伤,促进SCI后的再生和功能恢复。
实验动物分为WT组(野生型)和KO组(敲基因型),所有实验均在两组之间同时比较进行。参照改良Allen打击法,建立C3敲基因小鼠脊髓撞击伤模型,撞击位置为T12,撞击强度为5g×6cm,在此基础上进行Basso, Beattie and Bresnahan (BBB)行为学评分,并在SCI后不同时间(1h、12h、24h)分别用TNF-α抗体、星形胶质细胞(astrocytes,AST)的标记物GFAP抗体以及再生抑制相关蛋白NgR抗体和RhoA抗体进行免疫组织化学染色,用western blot检测SCI后1h、2h、6h、12h、24h TNF-α蛋白的表达,RT-PCR检测SCI后24h RhoA mRNA的表达,用神经元的标记物NF-200抗体检测SCI后14d和21d神经纤维再生情况,观察敲除补体C3基因对SCI后炎症因子TNF-α的表达、AST的活化、神经纤维的再生以及再生抑制相关蛋白NgR、RhoA表达的影响,以此验证通过敲除补体C3基因来抑制炎症反应、减轻继发性损伤从而促进再生的可行性。为了排除实验动物个体差异和在体诸多干扰因素的影响,又设计了体外实验。首先纯化培养AST和神经元,达到一定生长状态后,用无菌注射器针头呈“#”字形划伤,建立离体培养AST和神经元机械性损伤模型,ELISA检测细胞损伤后不同时间(1h、2h、6h、12h、24h、48h)培养上清中TNF-α的分泌情况,以验证C3基因敲除对炎症反应的抑制。随后将小鼠背根神经节(dorsal root ganglion, DRG)与机械划伤后的AST共培养,分别于1d、2d、3d、4d观察DRG神经突起生长状况。
主要结果:
1、建立了小鼠脊髓撞击伤模型,撞击位置为T12,撞击强度为5g×6cm,SCI后小鼠呈现典型的截瘫症状;
2、SCI后,WT组和KO组24h内病理学观察结果相似:损伤区结构破坏,灰质多灶性出血,损伤中心出现空腔,面积随时间延长逐渐增大;
3、SCI后,KO组小鼠BBB评分明显高于WT组,21d时KO组得分为17±0.8,已接近正常小鼠,而WT组得分仅为11±0.2;
4、Western blot和TNF-α免疫组织化学结果均表明,与WT组相比,KO组SCI后各时间点TNF-α免疫反应阳性细胞数目与免疫反应强度均比较稳定,高于KO组假手术对照,低于WT组表达的最高峰(6h);
5、KO组小鼠SCI后,活化AST数目和活化持续时间明显减少;
6、SCI后KO组小鼠再生神经纤维密度和长度均明显优于WT组;
7、SCI后,KO组再生抑制相关蛋白NgR、RhoA等的表达均有升高,但与WT组无明显区别。而western blot结果却表明SCI后,虽然WT组RhoA mRNA的表达升高,但KO组却并未升高;
8、ELISA检测AST和神经元机械性损伤模型上清液中TNF-α含量,发现机械性损伤后,无论是AST还是神经元,WT组TNF-α的表达在1h至48h均显著增加(p<0.05),6h达到最高峰。而KO组TNF-α的表达量未见显著升高;
9、建立了DRG与AST机械性损伤模型共培养体系,发现DRG + AST(WT,未损伤)和DRG + AST(KO,未损伤)两组中的DRG神经突起生长状况最好,突起长,密度大。DRG + AST(WT,损伤)和DRG + AST(KO,损伤)两组中的DRG神经突起生长都受到了抑制,前者受到的抑制作用最明显,神经突起长度最短,密度最小;后者受到的抑制作用较小,神经突起长度和密度介于DRG + AST(WT/KO,未损伤)和DRG + AST(WT,损伤)之间。
主要结论:
1. C3基因敲除能够有效抑制小鼠SCI后炎症因子TNF-α的表达,减轻炎症反应;
2. C3基因敲除能够减少活化AST数目和持续时间,有利于减少炎症因子的释放、减轻继发性损伤、改善再生环境,促进神经再生和功能恢复;
3. C3基因敲除后,小鼠神经纤维再生情况得到显著改善,运动能力得到较好恢复;
4. C3基因敲除能够抑制体外培养的AST和神经元分泌TNF-α,有效改善神经突起生长的微环境,促进再生。
总之,本研究通过建立C3敲基因小鼠脊髓撞击伤模型和DRG与AST机械性损伤模型共培养体系,运用免疫组织化学法、免疫荧光双标、western blot、RT-PCR、细胞培养以及ELISA等方法,证明敲除补体C3基因能够在一定程度上抑制炎症反应,减轻继发性损伤,促进神经再生和功能恢复。说明通过阻断补体系统激活来促进SCI后的神经再生与功能恢复不失为一条可行的新途径,为研究脊髓继发性损伤、促进CNS再生提供了新思路。
Spinal cord injury (SCI) has being paid much attention for its high deformity and mortality rates. The ultimate impairment of SCI is caused by two mechanisms, that is, initial injury and secondary injury. The former includes mechanical pressure, hemorrhage, electrolyte overflow and etc. The latter includes the impairment from edema, inflammation, local ischema, growth factors, cytokines, Ca2+ overflow and the abnormal change of peroxide radicles. These years the research about SCI has been focused on the tissue regeneration during the late stage of injury, for example, the transplantation of neural stem cells or olfactory ensheath cells, with not many effects. The main reason is that the secondary injury is neglected and the survived neurons during early stage of injury are not protected in time. These lead to the lack of innate condition for regeneration. As for SCI, the initial injury is a process that cannot be reversed, while the secondary injury is a process that can be reversed and controled. So more and more attention has been paid to alleviate the secondary injury through kinds of methods such as reducing inflammation.
There is an important inflammation process during the early phase of secondary injury which can lead to a series of reactions being harmful to the cells at the injury site. Besides, inflammation can result in the formation of glial scar which inhibits regeneration. Reducing inflammation can improve regeneration and functional recovery of central nervous system (CNS). It is worthy of notice that inflammation can activate complement system, and the activated complement segments can induce inflammation and aggravate the secondary injury to self tissues. Can we reduce inflammation through inhibiting the activation of complement system? How can we do it? We choose to knock out the C3 gene. Because C3 is a pivotal factor in complement activate pathways and is necessary for activation of complement system. In this study, our objective is to knock out the C3 gene to reduce inflammation and secondary injury to improve regeneration and functional recovery after SCI.
Animals were divided into WT group (wide type) and KO group (knock out type). All experiments were done at the same time between these two groups. Allen`s weight-drop method was adopted to establish the C3 deficient mouse spinal cord contusion model. By Basso, Beattie and Bresnahan (BBB) score method we observed the functional recovery of SCI mouse. By immunohistochemstry staining method, western blot, RT-PCR, we observed the expression of TNF-α, the activation of astrocytes (AST), the expression of regeneration inhibitory factors NgR and RhoA and the regeneration of nerve fibers. To exclude the individual differences of animals and interferential factors in vivo, we established AST and neuron mechanical injury models and detected their secretion of TNF-αat different time points. After that dosal root ganglions (DRG) were cocultured with AST mechanical injury model and the growth of DRG neurites were detected on different culture days.
Main results:
1. A mouse spinal cord weight-drop contusion model(5g×6cm) was established. The contused site was at T12. Typical paraplegia symptoms were occurred;
2. Both WT and KO mice showed similar pathological results after SCI: the spinal cord fabric at injury site was damaged, lots of hemorrhagic foci could be detected mainly in grey matter, and cavums appeared at injury centre with extendting areas;
3. The BBB score of KO mice after SCI was higher than WT mice obviously. The score of KO mice on 21d was 17±0.8, which was close to normal mice, while the WT mice just get 11±1.2 at the same time;
4. Western blot and immunohistochemistry showed that the number of TNF-αpositive cells and immunohistohemical intensity of KO mice after SCI were stable and higher than KO mice with sham operation but lower than WT mice at 6h;
5. The activated AST number and its activating duration of KO mice decreased obviously after SCI when compared to WT mice;
6. The length and density of regenerating neural fibers of KO mice after SCI were higher than WT mice obviously;
7. The immunohistochemistry staining method showed that the expression of NgR and RhoA were enhanced after SCI in KO mice, with no obvious difference to WT mice however. Western blot showed that the expression of RhoA mRNA in WT mice increased after SCI, but not in KO mice;
8. TNF-αsecreted by AST or neurons was detected by ELISA after mechanical injury. Its secretion in WT mice, whether from AST or neurons, increased during 1h to 48h, with peak at 6h. However, the secretion in KO mice did not increase;
9. DRG was cocultured with AST mechanical injury model. The length and density of neurites growth from DRG were measured. DRG+AST(WT , uninjured)and DRG+AST(KO,uninjured)groups had the longest and densest neurites. DRG+AST(WT, injured) group had the shortest and sparsest neurites. As for DRG+AST(KO, injured), its length and density of neurites were between DRG+AST(WT/KO, uninjured) and DRG+AST(WT, injured).
Main conclusions:
1. C3 knock-out can inhibit the expression of TNF-αafter SCI and reduce inflammation;
2. C3 knock-out can reduce the activated AST number and its activating duration, which is favorable to reduce inflammation, alleviate secondary injury and improve the regeneration environment;
3. C3 knock-out can improve the neurite regeneration and functional recovery after SCI;
4. C3 knock-out can inhibit the TNF-αsecreted by AST and neurons in vitro and promote neurite outgrowth.
In conclusion, our study showed that C3 gene knock-out can inhibit inflammation to some degree, reduce the secondary injury and improve the neurite regeneration and functional recovery after SCI. It is a new feasible way to promote the regeneraton of CNS through inhibiting the activation of complement system.
在继发性损伤早期,存在一个重要的炎症反应过程,它能触发其后发生的一系列针对受损部位细胞和分子水平的反应;此外,炎症反应可以导致受损局部胶质瘢痕的形成,从而进一步阻碍再生。抑制炎症反应能够促进中枢神经系统(central nervous system, CNS)的再生与功能恢复。值得注意的是,炎症过程引起了补体系统的激活,激活的补体片段又能通过多种途径导致炎症反应,对自身组织成分造成损害,加重SCI后的继发性损伤。那么是否可以通过阻断补体系统的激活来抑制炎症反应,从而减轻SCI后的继发性损伤呢?通过何种方式才能阻断补体系统的激活呢?我们选择敲除补体C3基因。因为已知补体系统的三条激活途径——包括经典途径、凝集素途径和旁路途径,虽然启动途径不同,但最后都汇集于一点,即C3转化酶对C3的分解,并在分解之后的活化过程中产生许多具有炎症介质作用的活性片断,如C3a、C4a和C5a等,最后进入共同的末端通路,形成攻膜复合体(membrane attack complx,MAC),并导致炎症反应。可见C3在补体系统已知的三条激活途径中处于枢纽地位,是补体系统激活的必要条件。本研究的目的就是通过敲除补体C3基因来抑制炎症反应,从而减轻继发性损伤,促进SCI后的再生和功能恢复。
实验动物分为WT组(野生型)和KO组(敲基因型),所有实验均在两组之间同时比较进行。参照改良Allen打击法,建立C3敲基因小鼠脊髓撞击伤模型,撞击位置为T12,撞击强度为5g×6cm,在此基础上进行Basso, Beattie and Bresnahan (BBB)行为学评分,并在SCI后不同时间(1h、12h、24h)分别用TNF-α抗体、星形胶质细胞(astrocytes,AST)的标记物GFAP抗体以及再生抑制相关蛋白NgR抗体和RhoA抗体进行免疫组织化学染色,用western blot检测SCI后1h、2h、6h、12h、24h TNF-α蛋白的表达,RT-PCR检测SCI后24h RhoA mRNA的表达,用神经元的标记物NF-200抗体检测SCI后14d和21d神经纤维再生情况,观察敲除补体C3基因对SCI后炎症因子TNF-α的表达、AST的活化、神经纤维的再生以及再生抑制相关蛋白NgR、RhoA表达的影响,以此验证通过敲除补体C3基因来抑制炎症反应、减轻继发性损伤从而促进再生的可行性。为了排除实验动物个体差异和在体诸多干扰因素的影响,又设计了体外实验。首先纯化培养AST和神经元,达到一定生长状态后,用无菌注射器针头呈“#”字形划伤,建立离体培养AST和神经元机械性损伤模型,ELISA检测细胞损伤后不同时间(1h、2h、6h、12h、24h、48h)培养上清中TNF-α的分泌情况,以验证C3基因敲除对炎症反应的抑制。随后将小鼠背根神经节(dorsal root ganglion, DRG)与机械划伤后的AST共培养,分别于1d、2d、3d、4d观察DRG神经突起生长状况。
主要结果:
1、建立了小鼠脊髓撞击伤模型,撞击位置为T12,撞击强度为5g×6cm,SCI后小鼠呈现典型的截瘫症状;
2、SCI后,WT组和KO组24h内病理学观察结果相似:损伤区结构破坏,灰质多灶性出血,损伤中心出现空腔,面积随时间延长逐渐增大;
3、SCI后,KO组小鼠BBB评分明显高于WT组,21d时KO组得分为17±0.8,已接近正常小鼠,而WT组得分仅为11±0.2;
4、Western blot和TNF-α免疫组织化学结果均表明,与WT组相比,KO组SCI后各时间点TNF-α免疫反应阳性细胞数目与免疫反应强度均比较稳定,高于KO组假手术对照,低于WT组表达的最高峰(6h);
5、KO组小鼠SCI后,活化AST数目和活化持续时间明显减少;
6、SCI后KO组小鼠再生神经纤维密度和长度均明显优于WT组;
7、SCI后,KO组再生抑制相关蛋白NgR、RhoA等的表达均有升高,但与WT组无明显区别。而western blot结果却表明SCI后,虽然WT组RhoA mRNA的表达升高,但KO组却并未升高;
8、ELISA检测AST和神经元机械性损伤模型上清液中TNF-α含量,发现机械性损伤后,无论是AST还是神经元,WT组TNF-α的表达在1h至48h均显著增加(p<0.05),6h达到最高峰。而KO组TNF-α的表达量未见显著升高;
9、建立了DRG与AST机械性损伤模型共培养体系,发现DRG + AST(WT,未损伤)和DRG + AST(KO,未损伤)两组中的DRG神经突起生长状况最好,突起长,密度大。DRG + AST(WT,损伤)和DRG + AST(KO,损伤)两组中的DRG神经突起生长都受到了抑制,前者受到的抑制作用最明显,神经突起长度最短,密度最小;后者受到的抑制作用较小,神经突起长度和密度介于DRG + AST(WT/KO,未损伤)和DRG + AST(WT,损伤)之间。
主要结论:
1. C3基因敲除能够有效抑制小鼠SCI后炎症因子TNF-α的表达,减轻炎症反应;
2. C3基因敲除能够减少活化AST数目和持续时间,有利于减少炎症因子的释放、减轻继发性损伤、改善再生环境,促进神经再生和功能恢复;
3. C3基因敲除后,小鼠神经纤维再生情况得到显著改善,运动能力得到较好恢复;
4. C3基因敲除能够抑制体外培养的AST和神经元分泌TNF-α,有效改善神经突起生长的微环境,促进再生。
总之,本研究通过建立C3敲基因小鼠脊髓撞击伤模型和DRG与AST机械性损伤模型共培养体系,运用免疫组织化学法、免疫荧光双标、western blot、RT-PCR、细胞培养以及ELISA等方法,证明敲除补体C3基因能够在一定程度上抑制炎症反应,减轻继发性损伤,促进神经再生和功能恢复。说明通过阻断补体系统激活来促进SCI后的神经再生与功能恢复不失为一条可行的新途径,为研究脊髓继发性损伤、促进CNS再生提供了新思路。
Spinal cord injury (SCI) has being paid much attention for its high deformity and mortality rates. The ultimate impairment of SCI is caused by two mechanisms, that is, initial injury and secondary injury. The former includes mechanical pressure, hemorrhage, electrolyte overflow and etc. The latter includes the impairment from edema, inflammation, local ischema, growth factors, cytokines, Ca2+ overflow and the abnormal change of peroxide radicles. These years the research about SCI has been focused on the tissue regeneration during the late stage of injury, for example, the transplantation of neural stem cells or olfactory ensheath cells, with not many effects. The main reason is that the secondary injury is neglected and the survived neurons during early stage of injury are not protected in time. These lead to the lack of innate condition for regeneration. As for SCI, the initial injury is a process that cannot be reversed, while the secondary injury is a process that can be reversed and controled. So more and more attention has been paid to alleviate the secondary injury through kinds of methods such as reducing inflammation.
There is an important inflammation process during the early phase of secondary injury which can lead to a series of reactions being harmful to the cells at the injury site. Besides, inflammation can result in the formation of glial scar which inhibits regeneration. Reducing inflammation can improve regeneration and functional recovery of central nervous system (CNS). It is worthy of notice that inflammation can activate complement system, and the activated complement segments can induce inflammation and aggravate the secondary injury to self tissues. Can we reduce inflammation through inhibiting the activation of complement system? How can we do it? We choose to knock out the C3 gene. Because C3 is a pivotal factor in complement activate pathways and is necessary for activation of complement system. In this study, our objective is to knock out the C3 gene to reduce inflammation and secondary injury to improve regeneration and functional recovery after SCI.
Animals were divided into WT group (wide type) and KO group (knock out type). All experiments were done at the same time between these two groups. Allen`s weight-drop method was adopted to establish the C3 deficient mouse spinal cord contusion model. By Basso, Beattie and Bresnahan (BBB) score method we observed the functional recovery of SCI mouse. By immunohistochemstry staining method, western blot, RT-PCR, we observed the expression of TNF-α, the activation of astrocytes (AST), the expression of regeneration inhibitory factors NgR and RhoA and the regeneration of nerve fibers. To exclude the individual differences of animals and interferential factors in vivo, we established AST and neuron mechanical injury models and detected their secretion of TNF-αat different time points. After that dosal root ganglions (DRG) were cocultured with AST mechanical injury model and the growth of DRG neurites were detected on different culture days.
Main results:
1. A mouse spinal cord weight-drop contusion model(5g×6cm) was established. The contused site was at T12. Typical paraplegia symptoms were occurred;
2. Both WT and KO mice showed similar pathological results after SCI: the spinal cord fabric at injury site was damaged, lots of hemorrhagic foci could be detected mainly in grey matter, and cavums appeared at injury centre with extendting areas;
3. The BBB score of KO mice after SCI was higher than WT mice obviously. The score of KO mice on 21d was 17±0.8, which was close to normal mice, while the WT mice just get 11±1.2 at the same time;
4. Western blot and immunohistochemistry showed that the number of TNF-αpositive cells and immunohistohemical intensity of KO mice after SCI were stable and higher than KO mice with sham operation but lower than WT mice at 6h;
5. The activated AST number and its activating duration of KO mice decreased obviously after SCI when compared to WT mice;
6. The length and density of regenerating neural fibers of KO mice after SCI were higher than WT mice obviously;
7. The immunohistochemistry staining method showed that the expression of NgR and RhoA were enhanced after SCI in KO mice, with no obvious difference to WT mice however. Western blot showed that the expression of RhoA mRNA in WT mice increased after SCI, but not in KO mice;
8. TNF-αsecreted by AST or neurons was detected by ELISA after mechanical injury. Its secretion in WT mice, whether from AST or neurons, increased during 1h to 48h, with peak at 6h. However, the secretion in KO mice did not increase;
9. DRG was cocultured with AST mechanical injury model. The length and density of neurites growth from DRG were measured. DRG+AST(WT , uninjured)and DRG+AST(KO,uninjured)groups had the longest and densest neurites. DRG+AST(WT, injured) group had the shortest and sparsest neurites. As for DRG+AST(KO, injured), its length and density of neurites were between DRG+AST(WT/KO, uninjured) and DRG+AST(WT, injured).
Main conclusions:
1. C3 knock-out can inhibit the expression of TNF-αafter SCI and reduce inflammation;
2. C3 knock-out can reduce the activated AST number and its activating duration, which is favorable to reduce inflammation, alleviate secondary injury and improve the regeneration environment;
3. C3 knock-out can improve the neurite regeneration and functional recovery after SCI;
4. C3 knock-out can inhibit the TNF-αsecreted by AST and neurons in vitro and promote neurite outgrowth.
In conclusion, our study showed that C3 gene knock-out can inhibit inflammation to some degree, reduce the secondary injury and improve the neurite regeneration and functional recovery after SCI. It is a new feasible way to promote the regeneraton of CNS through inhibiting the activation of complement system.
引文
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