腹主动脉瘤小鼠模型的病理形态学比较及抗血管紧张素治疗在其发病过程中的研究
发布时间：2018-08-22 21:30
【摘要】：第一章三种腹主动脉瘤小鼠模型的建立以及比较 目的：建立三种小鼠腹主动脉瘤(AAA)模型,比较三种建模方法的不同特点,探讨其研究应用的可行性。 方法：取C57BL/6以及ApoE-/-雄性小鼠共30只,采用三种不同方法分别建立三种小鼠腹主动脉瘤模型：血管紧张素Ⅱ模型[Angiotensin Ⅱ (Ang Ⅱ) Model],猪胰蛋白酶模型[Porcine Pancreatic Elastase(PPE) Model],氯化钙模型[Calcium Chloride (CaCl2) Model];并用磷酸缓冲溶液(PBS)作为相应方法的对照。多普勒超声监测小鼠腹主动脉直径变化、成瘤部位,计算并比较不同小鼠腹主动脉瘤模型的建模方法、手术时间、成瘤时间、成瘤率以及死亡率等特点； 结果：三种方法均能建立成功的腹主动脉瘤模型。PPE模型建模方法难度较大,手术时间较长(52.6±5.1min),成瘤率高(100%),存活周期长(随访4周,存活率为95%),死亡率低(5%)；CaC12模型建模方法容易,手术时间较长(40.7±4.3min),成瘤率较低(50%),存活周期长(随访4周均存活,存活率为100%),死亡率低(0%)；AngⅡ模型建模方法容易,手术时间短(7.8±3.6min),成瘤率较高(70%),存活周期较短(随访4周,存活率为60%),死亡率较高(40%)。 结论：小鼠的PPE模型,CaC12模型以及Ang Ⅱ模型为三种较为稳定的腹主动脉瘤模型,能为深入理解人腹主动脉瘤的病理机制以及评价腹主动脉瘤的药物治疗提供较为稳定的研究平台。 第二章三种腹主动脉瘤小鼠模型的病理形态学比较以及病理机制的研究 目的：观察不同小鼠模型的病理形态学特点,探讨不同腹主动脉瘤模型的共同病理机制。 方法：采用HE染色、EVG染色、免疫组织化学等方法检测小鼠的腹主动脉瘤组织,与正常小鼠腹主动脉相比较,观察病组织中瘤壁弹性纤维、炎症细胞、新生血管、淋巴管生成等的表达差异。 结果：PPE模型腹主动脉瘤病理变化表现为外膜大量炎症细胞浸润(尤其以巨噬细胞为主,伴有T淋巴细胞以及少量B淋巴细胞)以及新生血管、淋巴管形成,弹力纤维变性,部分缺失断裂,厚度不均。Ang Ⅱ模型表现为瘤壁血肿形成,外膜有炎症细胞浸润(以巨噬细胞为主,少有T淋巴细胞及B淋巴细胞)以及少量新生血管、淋巴管形成。伴有部分弹力纤维变性,缺失。CaCl2模型病变部位主要在外膜和中膜,表现为外膜部分增厚,伴少量炎症细胞浸润,仅有少量新生血管及淋巴管形成,中膜弹性纤维变性,僵直,呈烧灼状,厚薄不均,部分缺失断裂。 结论：三种小鼠模型既存在不同的病理形态学特点,也存在共同病理形态学特征,表现为炎症细胞浸润,血管及淋巴管生成。PPE、AngⅡ模型较为真实的反映了人腹主动脉瘤的病理特点,是两种比较稳定的动物模型。 第三章抗血管紧张素治疗在腹主动脉瘤发生发展过程中的研究 目的：将血管紧张素受体阻滞剂应用于小鼠腹主动脉瘤模型,评价抗血管紧张素治疗在腹主动脉瘤中的应用价值。 方法：取C57BL/6小鼠、ApoE-/-小鼠各15只,分成实验组(10只/组)和对照组(5只/组),实验组在建模前一周按telmisartan (10mg/kg)剂量给小鼠喂药；另一组为对照组,正常饮食。分别用多普勒超声监测小鼠的腹主动脉直径变化,与对照组(未用药处理的腹主动脉瘤模型小鼠)相比较,比较不同小鼠的成瘤率,瘤体进展情况等。并应用HE染色、EVG染色、免疫组织化学、qRT-PCR等方法检测腹主动脉瘤组织,比较不同小鼠的病理形态学变化。 结果：telmisartan在10mg/kg的剂量下对小鼠无明显副作用,能够有效抑制弹力蛋白酶及血管紧张素灌注后的小鼠腹主动脉直径进行性增大,并且能够防止两种腹主动脉瘤小鼠模型的腹主动脉瘤形成。病理切片显示：telmisartan处理过的小鼠主动脉管壁血管生成明显减少,炎症细胞浸润显著减轻,弹性纤维以及管壁三层结构相对完整,无显著病理变化。 结论：抗血管紧张素治疗能够防止小鼠腹主动脉瘤的发生并控制疾病的进展。telmisartan能够发挥有效的抗动脉瘤生成作用；10mg/kg的剂量安全,有效。
[Abstract]:Chapter 1 Establishment and comparison of three abdominal aortic aneurysm models in mice
Objective: To establish three models of abdominal aortic aneurysm (AAA) in mice and compare the different characteristics of the three models and explore the feasibility of their application.
Methods: C57BL/6 and ApoE-/- male mice were used to establish three kinds of abdominal aortic aneurysm models: Angiotensin II (AngII) model, Porcine Pancreatic Elastase (PPE) model and Calcium Chloride (CaCl2) model. Doppler ultrasonography was used to monitor the abdominal aorta diameter, tumor location, and to calculate and compare the modeling methods, operation time, tumor formation time, tumor formation rate and mortality of abdominal aorta aneurysm models in different mice.
Results: All three methods can establish successful abdominal aortic aneurysm models. PPE modeling method is difficult, the operation time is long (52.6 65 Ang II model has the advantages of easy modeling, short operation time (7.8 (+ 3.6 min), high tumor formation rate (70%), short survival period (60%) and high mortality (40%).
CONCLUSION: The PPE model, CaC12 model and Ang II model in mice are relatively stable models of abdominal aortic aneurysm, which can provide a stable research platform for further understanding the pathological mechanism of human abdominal aortic aneurysm and evaluating the drug treatment of abdominal aortic aneurysm.
The second chapter is about the pathomorphology comparison and pathological mechanism of three abdominal aortic aneurysm models in mice.
Objective: To observe the pathomorphological characteristics of different mouse models and explore the common pathological mechanism of different abdominal aortic aneurysm models.
Methods: HE staining, EVG staining and immunohistochemistry were used to detect the abdominal aortic aneurysm in mice. The expression of elastic fibers, inflammatory cells, neovascularization and lymphangiogenesis in the abdominal aorta of mice were compared with those of normal mice.
Results: The pathological changes of abdominal aortic aneurysm in PPE model were infiltration of a large number of inflammatory cells in the adventitia (especially macrophages with T lymphocytes and a small number of B lymphocytes) and neovascularization, lymphangiogenesis, elastic fibrosis, partial loss and rupture, and uneven thickness. The lesions in the CaCl2 model were mainly in the adventitia and mesangium, which showed partial thickening of the adventitia with a small amount of inflammatory cell infiltration, only a small amount of neovascularization and lymphatic vessel formation. The elastic fibers of the medial membrane are degenerated and stiff, with cauterization, uneven thickness and partial absence of fracture.
CONCLUSION: The three mouse models have different pathomorphological characteristics as well as common pathomorphological characteristics, such as inflammatory cell infiltration, angiogenesis and lymphangiogenesis. PPE and Ang II models reflect the pathological characteristics of human abdominal aortic aneurysm, and are two relatively stable animal models.
The third chapter is the study of anti angiotensin therapy in the development of abdominal aortic aneurysm.
AIM: To evaluate the value of antiangiotensin therapy in abdominal aortic aneurysm (AAA) by using angiotensin receptor blockers in mice.
METHODS: C57BL/6 mice and ApoE-/- mice were divided into experimental group (10 mice/group) and control group (5 mice/group), the experimental group was given telmisartan (10 mg/kg) one week before modeling, and the control group was given normal diet. The tumorigenesis rate and tumor progression of different mice were compared, and the abdominal aortic aneurysm tissues were detected by HE staining, EVG staining, immunohistochemistry, qRT-PCR and other methods.
Results: telmisartan had no obvious side effect on mice at the dose of 10 mg/kg. It could effectively inhibit the progressive enlargement of abdominal aorta diameter in mice perfused with elastase and angiotensin, and prevent the formation of abdominal aortic aneurysm in two kinds of abdominal aortic aneurysm mice. Vasculogenesis of aortic wall was significantly reduced, inflammatory cell infiltration was significantly reduced, elastic fibers and three-layer structure of aortic wall were relatively intact without significant pathological changes.
Conclusion: Antiangiotensin therapy can prevent the occurrence of abdominal aortic aneurysm and control the progress of the disease in mice.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R732.21;R-332
本文编号：2198351
[Abstract]:Chapter 1 Establishment and comparison of three abdominal aortic aneurysm models in mice
Objective: To establish three models of abdominal aortic aneurysm (AAA) in mice and compare the different characteristics of the three models and explore the feasibility of their application.
Methods: C57BL/6 and ApoE-/- male mice were used to establish three kinds of abdominal aortic aneurysm models: Angiotensin II (AngII) model, Porcine Pancreatic Elastase (PPE) model and Calcium Chloride (CaCl2) model. Doppler ultrasonography was used to monitor the abdominal aorta diameter, tumor location, and to calculate and compare the modeling methods, operation time, tumor formation time, tumor formation rate and mortality of abdominal aorta aneurysm models in different mice.
Results: All three methods can establish successful abdominal aortic aneurysm models. PPE modeling method is difficult, the operation time is long (52.6 65 Ang II model has the advantages of easy modeling, short operation time (7.8 (+ 3.6 min), high tumor formation rate (70%), short survival period (60%) and high mortality (40%).
CONCLUSION: The PPE model, CaC12 model and Ang II model in mice are relatively stable models of abdominal aortic aneurysm, which can provide a stable research platform for further understanding the pathological mechanism of human abdominal aortic aneurysm and evaluating the drug treatment of abdominal aortic aneurysm.
The second chapter is about the pathomorphology comparison and pathological mechanism of three abdominal aortic aneurysm models in mice.
Objective: To observe the pathomorphological characteristics of different mouse models and explore the common pathological mechanism of different abdominal aortic aneurysm models.
Methods: HE staining, EVG staining and immunohistochemistry were used to detect the abdominal aortic aneurysm in mice. The expression of elastic fibers, inflammatory cells, neovascularization and lymphangiogenesis in the abdominal aorta of mice were compared with those of normal mice.
Results: The pathological changes of abdominal aortic aneurysm in PPE model were infiltration of a large number of inflammatory cells in the adventitia (especially macrophages with T lymphocytes and a small number of B lymphocytes) and neovascularization, lymphangiogenesis, elastic fibrosis, partial loss and rupture, and uneven thickness. The lesions in the CaCl2 model were mainly in the adventitia and mesangium, which showed partial thickening of the adventitia with a small amount of inflammatory cell infiltration, only a small amount of neovascularization and lymphatic vessel formation. The elastic fibers of the medial membrane are degenerated and stiff, with cauterization, uneven thickness and partial absence of fracture.
CONCLUSION: The three mouse models have different pathomorphological characteristics as well as common pathomorphological characteristics, such as inflammatory cell infiltration, angiogenesis and lymphangiogenesis. PPE and Ang II models reflect the pathological characteristics of human abdominal aortic aneurysm, and are two relatively stable animal models.
The third chapter is the study of anti angiotensin therapy in the development of abdominal aortic aneurysm.
AIM: To evaluate the value of antiangiotensin therapy in abdominal aortic aneurysm (AAA) by using angiotensin receptor blockers in mice.
METHODS: C57BL/6 mice and ApoE-/- mice were divided into experimental group (10 mice/group) and control group (5 mice/group), the experimental group was given telmisartan (10 mg/kg) one week before modeling, and the control group was given normal diet. The tumorigenesis rate and tumor progression of different mice were compared, and the abdominal aortic aneurysm tissues were detected by HE staining, EVG staining, immunohistochemistry, qRT-PCR and other methods.
Results: telmisartan had no obvious side effect on mice at the dose of 10 mg/kg. It could effectively inhibit the progressive enlargement of abdominal aorta diameter in mice perfused with elastase and angiotensin, and prevent the formation of abdominal aortic aneurysm in two kinds of abdominal aortic aneurysm mice. Vasculogenesis of aortic wall was significantly reduced, inflammatory cell infiltration was significantly reduced, elastic fibers and three-layer structure of aortic wall were relatively intact without significant pathological changes.
Conclusion: Antiangiotensin therapy can prevent the occurrence of abdominal aortic aneurysm and control the progress of the disease in mice.
【学位授予单位】：中南大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R732.21;R-332
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