细胞凋亡在慢病毒介导hVEGF165-GFP基因转染内皮祖细胞移植治疗MODS中变化的研究
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摘要
多器官功能障碍综合症(multiple organ dysfunction syndrome, MODS)是重症监护病房患者的最常见死亡原因。严重的感染和感染性休克是其主要诱因。感染所致的脓毒症及非感染所致的全身炎症反应综合征(systemic inflammatory response syndrome, SIRS)相互作用,构成了一个复杂的网络。目前其发病机制尚不完全明确,临床上尚缺乏满意的治疗措施。随着干／祖细胞研究的不断深入,多器官功能障碍综合征的发病机制研究和临床治疗面临着新的契机。
近年来研究发现：骨髓中有一群能够在生理性或病理性因素的刺激下,动员到外周血并分化为成熟内皮细胞(Endothelium cell, EC)以促进血管新生,并可以分化为相应的组织细胞进行损伤修复的祖细胞,这些细胞被称为内皮祖细胞(Endothelial progenitor cells, EPCs)。EPC过去被认为是胚胎时期血管新生最主要的细胞,而越来越多的证据显示EPCs也是出生后生理性及病理性血管形成最主要的细胞,并参与心、肝、肺、肾等单个器官障碍时的修复；同时迁徙到损伤部位的EPC还可以对不同的局部刺激(包括缺氧或缺血)作出生理反应,依次释放血管活性物质、生长因子以及参与免疫调节的细胞因子和趋化因子,参与创伤后的炎症反应。
同时研究发现内皮细胞不仅是炎症反应的参与者,还是首先受损的靶细胞,并进而造成微血管损伤、微循环障碍,这可能是器官功能障碍的始发环节。大量的动物和临床实验都已经证明：当组织受到损伤时,尤其是缺血性损伤时,循环及组织中EPCs动员和增殖能力增强,并可以在组织内分化为内皮细胞替换功能障碍的内皮细胞、修补裸露的血管内皮损伤区,并参与缺血或损伤组织内新血管生成,从而改善缺血器官的功能；而如果创伤后EPCs的分化、迁徙功能发生严重障碍,则会导致损伤微循环严重损害而无法得到修复,甚至发生器官功能衰竭。
既往研究发现与MODS有关的细胞因子有白介素(IL-1,IL-6)、肿瘤坏死因子(TNF)、热休克蛋白(HSP)、糖皮质激素和细菌产物如内毒素等,它们在导致SIRS/MODS细胞凋亡中具有潜在作用。通过对某些重要器官的细胞凋亡机制及其影响因素的研究可以更深入的了解MODS的机理,为临床更好的防治MODS提供实验依据。
本研究通过内毒素+失血性休克制造出MODS的动物模型,在此基础上进行慢病毒介导VEGF-GFP基因转染EPCs移植治疗,动态观察移植前后动物生命体征的变化,血浆中IL-1β、TNF-α等炎性因子表达的变化,以及主要脏器的细胞凋亡情况,评价移植EPC防治MODS的效果,并对其作用机制进行初步探讨。全文共分四部分。
第一部分目的：复制双相迟发型的兔MODS模型,为研究移植内皮祖细胞防治创伤后多器官功能障碍的研究提供实验基础。方法：将体重2.52±0.27Kg健康雄性家兔随机分为2组：实验组(M组)12只,施行失血性休克+内毒素血症复合因素；对照组(C)12只,施行假手术,予以股动静脉置管,不实施失血及内毒素注射。用自动分析仪检测WBC、GRAN、SALT、SAST、Cr、BUN、动脉血氧分压(PaO2),以判断器官功能,7天后处死存活动物,观察主要脏器的病理改变。结果：实验组(M组)WBC、GRAN、SALT、SAST、Cr、BUN均明显升高,动物死亡前显著高于正常值,PaO2明显下降。病理学改变主要表现为衰竭器官呈以炎症为主的非特异性改变。实验组MODS发生率为83.3%,死亡率为75%,显著高于对照组。结论：本实验采用二次打击方法,与临床实际相符,并且MODS的发生率及死亡率均高,操作简单,容易复制,是一个较成功的动物模型。
第二部分目的：制备携带hVEGF165-GFPs双表达基因的慢病毒载体,体外转染内皮祖细胞,为EPC移植治疗做准备。方法：将目的基因VEFG165插入慢病毒过表达载体pWPXL-MOD,慢病毒包装质粒转染293T细胞,得到LV/hVEGF165-GFP,将LV/hVEGF165-GFP与EPCs共培养以转染EPCs。对LV/hVEGF165-GFP-EPCs进行其黏附、迁徙、增殖和血管生成功能进行检测。结果：慢病毒载体能表达目的基因VEGF,成功构建和包装了慢病毒载体；并证实EPCs经LV/hVEGF165-GFP转染后转染率达99%。其迁徙、增殖和血管生成等功能较未转染EPCs提高,P<0.05。结论：LV/hVEGF165-GFP对细胞无毒性,且能提高EPCs的粘附、迁徙及增殖能力。
第三部分目的：研究细胞凋亡在慢病毒介导VEGF165-GFP基因转染EPCs移植治疗MODS中的变化及意义。方法：将体重2.52±0.27Kg健康雄性家兔随机分为3组：单纯MODS组(M)12只,施行失血性休克+内毒素复合因素；单纯内皮祖细胞移植组(ET)12只和慢病毒介导VEGF165-GFP基因转染内皮祖细胞移植组(VT)12只,在固定时间点,分别以1×107个细胞／Kg(体重)和1×107个转染后细胞／Kg(体重)的剂量进行移植治疗。用自动分析仪检测WBC、GRAN、SALT、SAST、Cr、BUN、动脉血氧分压(PaO2),以判断器官功能,7天后处死存活动物,观察主要脏器的病理改变。原位末端(TUNEL)法检测主要脏器细胞凋亡情况。RT-PCR法检测主要脏器caspase3mRNA表达情况。结果：VT组WBC、GRAN、GOT、GPT、Cr、BUN等指标在移植治疗后较M组及ET组均有明显改善,比较有统计学意义。VT组主要脏器细胞凋亡及caspase3mRNA表达均低于M组及ET组,P<0.01。VT组动物的MODS发生率和死亡率较M组及ET组明显减少,P<0.05。结论：移植慢病毒介导VEGF165-GFP基因转染EPCs治疗MODS,能减少MODS动物的细胞凋亡,明显的改善各个重要脏器的功能,降低动物的死亡率。
Multiple organ dysfunction syndrome (MODS) is the most frequent cause of death in patients admitted to intensive care units. Severe sepsis and septic shock are the primary causes of MODS and develop as a result of the host response to infection of Gram-neagitve and Gram-positive bacteria. Infections sepsis and nonsepsis systemic inflammatory response syndrome (SIRS) encompass a complex mosaic of interconnected events. The pathogenesis of MODS is not clear and there are not satisfactory therapic methods in clinic at present. With the development of clinical technologies of progenitor cells, the moment emerged in pathogenesis reaserchs and clinical therapy of MODS
Recent research shows that EPC is one kind of progenitor cells from bone marrow which can be mobilized by physio-stimulation and patho-stimulation to peripheral blood to differentiate into mature endothelial cells (EC) to encourage angiogenesis and differentiate to different kind of cells to process repairing. EPCs were originally thought to be present only during embryonic development. However, accumulating evidence in the past several years suggested that EPCs were the major progenitor cells to participate inphysio-angiogenesis and patho-angiogenesis in adult lives. EPCs could particate in reparing of dysfunctions of heart、renal、liver and pulmonary and the EPCs which metastasized to pars affecta could be reacted to release the vasoactive substance、growth factors、immunoregulatory cytokines and chemotatic factors.
Also research finds that the endothelial cells are not only the damaged target cells, but also causes of blood capillary damage and dysfunction or the first component element of MODS. The massive animal and clinical experiments have already certificated that when tissues is damaged, especially ischemia, the proliferation, migration, differentiation of EPCs are reinforced into peripheral blood and turn into endothelial cells and replace the damaged endothelial cells in tissue. The denuded damaged vessel is repaired by new endothelial cells. EPCs can participate neovascularity in ischemia or damaged tissue and improve ischemia organs' function. If the proliferation, migration and differentiation of EPCs are seriously disturbanced after trauma, they would make the microcirculation unrepaired and MODS come bad to worse.
Past studies showed that the cytokines related to MODS were concluded IL-1, IL-6, TNF, HSP, Glucocorticoid, LPS, and so on. They were associated with apoptosis. So we may be more in-depth understanding of the mechanism of MODS by studying the mechanism and influencing factors of apoptosis and provide the basis for clinical.
The study was to replicate a rabbit model of MODS, and then did transplantation of EPCs transfected with LV/VEGF165-GFP gene. Then we observed vital signs of major organs and the expression of inflammatory cytokines, such as IL-1β, TNF-αand so on. Our purpose was to find the effect of the EPCs to prevent and treat MODS. The study includes three main parts.
Part 1 Objective:To replicate a rabbit model of MODS which was characterized by the development of delayed two-phase process and it was the foundation of our investigation of transplantation of EPCs to prevent and treat MODS. Methods: Twenty-four healthy male rabbits weighing 2.25～2.79Kg were divided into two groups randomly. One group was subjected to hemorrhagic shock plus endotoxiemia (group M, n=12). Another group was normal control only with anesthesia and sham operation (group C, n=12). Blood specimens were collected every 24 hours during the seven-day observation for the detection of serum GPT, GOT, Cr, BUN and arterial blood gas analysis, which were used to judge if MODS occured by compared with the initial value of itself. Histological changes of the main organs were observed under light microscope (LM). Results:The mobidity and mortality of MODS in group M were 83.3% and 75.0% respectively, both much higher than group C. Conclusion:The two-hit model of MODS was a successful animal model which conforms to clinical course, also with high mobidity and mortality. And the model was easy to duplicate.
Part 2 Objective:To construct the Lentivirus carrying hVEGF165-GFP gene, and transfect endothelial progenitor cells in vitro. Methods:The VEGF165 gene was ligated into the lentiviral overexpression vector pWPXL-MOD. Then we used lentiviral packaging plasmid to transfect 293T cells and got the LV/hVEGF165-GFP. The LV/hVEGF165-GFP was co-cultured with EPCs. Adhesion, migration, proliferation and angiogenesis function were observed after tranfected. Results:Lentiviral vector expressing the target gene VEGF was successfully constructed. It confirmed that the LV/hVEGF165-GFP's transfection rate was nearly 99%. After transfected, EPCs' migration, proliferation and angiogenesis were increased (P<0.05). Conclusion:LV/hVEGF165-GFP was non-toxic to EPCs, and can improve the EPCs' adhesion, migration and proliferation ability.
Part 3 Objective:To study the change of apoptosis in rabbits of multiple organ dysfunction syndrome by transplanting of endothelial progenitor cells transfected with LV/VEGF165-GFP gene. Methods:Thirty-six healthy male rabbits weighing 2.25～ 2.79Kg were divided into three groups randomly. One group was subjected to hemorrhagic shock plus endotoxiemia (group M, n=12), the group with no transplantation as the control group. Another group (group ET, n=12) was transplanted of EPCs with the 1×107 cells/ Kg body weight. The other group (group VT, n=12) was transplanted of EPCs transfected with LV-VEGF165-GFP gene with the 1 x 107 cells/Kg body weight. Blood specimens were collected every 24 hours during the seven-day observation for the detection of serum GPT, GOT, Cr, BUN and arterial blood gas analysis. Histological changes of the main organs were observed under light microscope. The apotosis of the main organs was tested by TUNEL. The caspase-3 mRNA of the main organs was measured by RT-PCR. Results: The WBC, GRAN, GOT, GPT, Cr, BUN and other indcators of VT group were significant improvement compared with ET group and M group. The apotosis and caspase3mRNA expression of main organs in VT group were lower than ET group and M group (P<0.01). The mobidity and mortality of VT group were lower than ET group and M group (P< 0.05). Conclusion:Transplantation of EPCs transfected with lentivirus-mediated VEGF165-GFP gene can reduce the MODS animal apoptosis, make a marked improvement of the function in main organs and reduce the animal's mortality.
近年来研究发现：骨髓中有一群能够在生理性或病理性因素的刺激下,动员到外周血并分化为成熟内皮细胞(Endothelium cell, EC)以促进血管新生,并可以分化为相应的组织细胞进行损伤修复的祖细胞,这些细胞被称为内皮祖细胞(Endothelial progenitor cells, EPCs)。EPC过去被认为是胚胎时期血管新生最主要的细胞,而越来越多的证据显示EPCs也是出生后生理性及病理性血管形成最主要的细胞,并参与心、肝、肺、肾等单个器官障碍时的修复；同时迁徙到损伤部位的EPC还可以对不同的局部刺激(包括缺氧或缺血)作出生理反应,依次释放血管活性物质、生长因子以及参与免疫调节的细胞因子和趋化因子,参与创伤后的炎症反应。
同时研究发现内皮细胞不仅是炎症反应的参与者,还是首先受损的靶细胞,并进而造成微血管损伤、微循环障碍,这可能是器官功能障碍的始发环节。大量的动物和临床实验都已经证明：当组织受到损伤时,尤其是缺血性损伤时,循环及组织中EPCs动员和增殖能力增强,并可以在组织内分化为内皮细胞替换功能障碍的内皮细胞、修补裸露的血管内皮损伤区,并参与缺血或损伤组织内新血管生成,从而改善缺血器官的功能；而如果创伤后EPCs的分化、迁徙功能发生严重障碍,则会导致损伤微循环严重损害而无法得到修复,甚至发生器官功能衰竭。
既往研究发现与MODS有关的细胞因子有白介素(IL-1,IL-6)、肿瘤坏死因子(TNF)、热休克蛋白(HSP)、糖皮质激素和细菌产物如内毒素等,它们在导致SIRS/MODS细胞凋亡中具有潜在作用。通过对某些重要器官的细胞凋亡机制及其影响因素的研究可以更深入的了解MODS的机理,为临床更好的防治MODS提供实验依据。
本研究通过内毒素+失血性休克制造出MODS的动物模型,在此基础上进行慢病毒介导VEGF-GFP基因转染EPCs移植治疗,动态观察移植前后动物生命体征的变化,血浆中IL-1β、TNF-α等炎性因子表达的变化,以及主要脏器的细胞凋亡情况,评价移植EPC防治MODS的效果,并对其作用机制进行初步探讨。全文共分四部分。
第一部分目的：复制双相迟发型的兔MODS模型,为研究移植内皮祖细胞防治创伤后多器官功能障碍的研究提供实验基础。方法：将体重2.52±0.27Kg健康雄性家兔随机分为2组：实验组(M组)12只,施行失血性休克+内毒素血症复合因素；对照组(C)12只,施行假手术,予以股动静脉置管,不实施失血及内毒素注射。用自动分析仪检测WBC、GRAN、SALT、SAST、Cr、BUN、动脉血氧分压(PaO2),以判断器官功能,7天后处死存活动物,观察主要脏器的病理改变。结果：实验组(M组)WBC、GRAN、SALT、SAST、Cr、BUN均明显升高,动物死亡前显著高于正常值,PaO2明显下降。病理学改变主要表现为衰竭器官呈以炎症为主的非特异性改变。实验组MODS发生率为83.3%,死亡率为75%,显著高于对照组。结论：本实验采用二次打击方法,与临床实际相符,并且MODS的发生率及死亡率均高,操作简单,容易复制,是一个较成功的动物模型。
第二部分目的：制备携带hVEGF165-GFPs双表达基因的慢病毒载体,体外转染内皮祖细胞,为EPC移植治疗做准备。方法：将目的基因VEFG165插入慢病毒过表达载体pWPXL-MOD,慢病毒包装质粒转染293T细胞,得到LV/hVEGF165-GFP,将LV/hVEGF165-GFP与EPCs共培养以转染EPCs。对LV/hVEGF165-GFP-EPCs进行其黏附、迁徙、增殖和血管生成功能进行检测。结果：慢病毒载体能表达目的基因VEGF,成功构建和包装了慢病毒载体；并证实EPCs经LV/hVEGF165-GFP转染后转染率达99%。其迁徙、增殖和血管生成等功能较未转染EPCs提高,P<0.05。结论：LV/hVEGF165-GFP对细胞无毒性,且能提高EPCs的粘附、迁徙及增殖能力。
第三部分目的：研究细胞凋亡在慢病毒介导VEGF165-GFP基因转染EPCs移植治疗MODS中的变化及意义。方法：将体重2.52±0.27Kg健康雄性家兔随机分为3组：单纯MODS组(M)12只,施行失血性休克+内毒素复合因素；单纯内皮祖细胞移植组(ET)12只和慢病毒介导VEGF165-GFP基因转染内皮祖细胞移植组(VT)12只,在固定时间点,分别以1×107个细胞／Kg(体重)和1×107个转染后细胞／Kg(体重)的剂量进行移植治疗。用自动分析仪检测WBC、GRAN、SALT、SAST、Cr、BUN、动脉血氧分压(PaO2),以判断器官功能,7天后处死存活动物,观察主要脏器的病理改变。原位末端(TUNEL)法检测主要脏器细胞凋亡情况。RT-PCR法检测主要脏器caspase3mRNA表达情况。结果：VT组WBC、GRAN、GOT、GPT、Cr、BUN等指标在移植治疗后较M组及ET组均有明显改善,比较有统计学意义。VT组主要脏器细胞凋亡及caspase3mRNA表达均低于M组及ET组,P<0.01。VT组动物的MODS发生率和死亡率较M组及ET组明显减少,P<0.05。结论：移植慢病毒介导VEGF165-GFP基因转染EPCs治疗MODS,能减少MODS动物的细胞凋亡,明显的改善各个重要脏器的功能,降低动物的死亡率。
Multiple organ dysfunction syndrome (MODS) is the most frequent cause of death in patients admitted to intensive care units. Severe sepsis and septic shock are the primary causes of MODS and develop as a result of the host response to infection of Gram-neagitve and Gram-positive bacteria. Infections sepsis and nonsepsis systemic inflammatory response syndrome (SIRS) encompass a complex mosaic of interconnected events. The pathogenesis of MODS is not clear and there are not satisfactory therapic methods in clinic at present. With the development of clinical technologies of progenitor cells, the moment emerged in pathogenesis reaserchs and clinical therapy of MODS
Recent research shows that EPC is one kind of progenitor cells from bone marrow which can be mobilized by physio-stimulation and patho-stimulation to peripheral blood to differentiate into mature endothelial cells (EC) to encourage angiogenesis and differentiate to different kind of cells to process repairing. EPCs were originally thought to be present only during embryonic development. However, accumulating evidence in the past several years suggested that EPCs were the major progenitor cells to participate inphysio-angiogenesis and patho-angiogenesis in adult lives. EPCs could particate in reparing of dysfunctions of heart、renal、liver and pulmonary and the EPCs which metastasized to pars affecta could be reacted to release the vasoactive substance、growth factors、immunoregulatory cytokines and chemotatic factors.
Also research finds that the endothelial cells are not only the damaged target cells, but also causes of blood capillary damage and dysfunction or the first component element of MODS. The massive animal and clinical experiments have already certificated that when tissues is damaged, especially ischemia, the proliferation, migration, differentiation of EPCs are reinforced into peripheral blood and turn into endothelial cells and replace the damaged endothelial cells in tissue. The denuded damaged vessel is repaired by new endothelial cells. EPCs can participate neovascularity in ischemia or damaged tissue and improve ischemia organs' function. If the proliferation, migration and differentiation of EPCs are seriously disturbanced after trauma, they would make the microcirculation unrepaired and MODS come bad to worse.
Past studies showed that the cytokines related to MODS were concluded IL-1, IL-6, TNF, HSP, Glucocorticoid, LPS, and so on. They were associated with apoptosis. So we may be more in-depth understanding of the mechanism of MODS by studying the mechanism and influencing factors of apoptosis and provide the basis for clinical.
The study was to replicate a rabbit model of MODS, and then did transplantation of EPCs transfected with LV/VEGF165-GFP gene. Then we observed vital signs of major organs and the expression of inflammatory cytokines, such as IL-1β, TNF-αand so on. Our purpose was to find the effect of the EPCs to prevent and treat MODS. The study includes three main parts.
Part 1 Objective:To replicate a rabbit model of MODS which was characterized by the development of delayed two-phase process and it was the foundation of our investigation of transplantation of EPCs to prevent and treat MODS. Methods: Twenty-four healthy male rabbits weighing 2.25～2.79Kg were divided into two groups randomly. One group was subjected to hemorrhagic shock plus endotoxiemia (group M, n=12). Another group was normal control only with anesthesia and sham operation (group C, n=12). Blood specimens were collected every 24 hours during the seven-day observation for the detection of serum GPT, GOT, Cr, BUN and arterial blood gas analysis, which were used to judge if MODS occured by compared with the initial value of itself. Histological changes of the main organs were observed under light microscope (LM). Results:The mobidity and mortality of MODS in group M were 83.3% and 75.0% respectively, both much higher than group C. Conclusion:The two-hit model of MODS was a successful animal model which conforms to clinical course, also with high mobidity and mortality. And the model was easy to duplicate.
Part 2 Objective:To construct the Lentivirus carrying hVEGF165-GFP gene, and transfect endothelial progenitor cells in vitro. Methods:The VEGF165 gene was ligated into the lentiviral overexpression vector pWPXL-MOD. Then we used lentiviral packaging plasmid to transfect 293T cells and got the LV/hVEGF165-GFP. The LV/hVEGF165-GFP was co-cultured with EPCs. Adhesion, migration, proliferation and angiogenesis function were observed after tranfected. Results:Lentiviral vector expressing the target gene VEGF was successfully constructed. It confirmed that the LV/hVEGF165-GFP's transfection rate was nearly 99%. After transfected, EPCs' migration, proliferation and angiogenesis were increased (P<0.05). Conclusion:LV/hVEGF165-GFP was non-toxic to EPCs, and can improve the EPCs' adhesion, migration and proliferation ability.
Part 3 Objective:To study the change of apoptosis in rabbits of multiple organ dysfunction syndrome by transplanting of endothelial progenitor cells transfected with LV/VEGF165-GFP gene. Methods:Thirty-six healthy male rabbits weighing 2.25～ 2.79Kg were divided into three groups randomly. One group was subjected to hemorrhagic shock plus endotoxiemia (group M, n=12), the group with no transplantation as the control group. Another group (group ET, n=12) was transplanted of EPCs with the 1×107 cells/ Kg body weight. The other group (group VT, n=12) was transplanted of EPCs transfected with LV-VEGF165-GFP gene with the 1 x 107 cells/Kg body weight. Blood specimens were collected every 24 hours during the seven-day observation for the detection of serum GPT, GOT, Cr, BUN and arterial blood gas analysis. Histological changes of the main organs were observed under light microscope. The apotosis of the main organs was tested by TUNEL. The caspase-3 mRNA of the main organs was measured by RT-PCR. Results: The WBC, GRAN, GOT, GPT, Cr, BUN and other indcators of VT group were significant improvement compared with ET group and M group. The apotosis and caspase3mRNA expression of main organs in VT group were lower than ET group and M group (P<0.01). The mobidity and mortality of VT group were lower than ET group and M group (P< 0.05). Conclusion:Transplantation of EPCs transfected with lentivirus-mediated VEGF165-GFP gene can reduce the MODS animal apoptosis, make a marked improvement of the function in main organs and reduce the animal's mortality.
引文
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