趋化因子受体CXCR2促进腹主动脉瘤发生的作用机制研究及血管生成素相关生长因子在腹主动脉瘤血浆中的变化
发布时间：2019-02-12 09:30
【摘要】：研究背景及目的：腹主动脉瘤(AAA)是老龄化社会的常见病,发病隐匿,一旦破裂,死亡率达60～80%。炎症、细胞外基质降解、平滑肌细胞(SMC)凋亡及表型转化、和氧化应激等均是AAA发生的关键环节。巨噬细胞浸润是腹主动脉瘤(AAA)进展的关键环节,趋化因子受体CXCR2及配体对巨噬细胞在组织的浸润起重要调节作用。但在AAA进展过程中,CXCR2如何调节巨噬细胞浸润,进而降解细胞外基质、引起氧化应激,机制尚不清楚。因此,本实验采用CXCR2特异性抑制剂SB265610抑制CXCR2表达,明确CXCR2对小鼠AAA形成的调节作用,阐明CXCR2促进AAA进展的具体分子机制。其次本实验收集AAA病人和正常人血浆,检测血管生成素相关生长因子并探讨其与腹主动脉瘤直径之间的关系。实验方法：(1)通过对雄性缺陷小鼠(ApoE-/-)皮下埋植血管紧张素Ⅱ (Ang Ⅱ)缓释泵(1,000 ng/min/kg)的方法,复制动物AAA模型； (2)通过腹腔注射SB265610 (2mg/kg·d)抑制CXCR2,因此小鼠分成四组：Control, SB265610, Ang Ⅱ, AngⅡ+SB265610。通过测量血管超声、鼠尾监测血压及大体解剖观察各组小鼠体内动脉大体形态及血压变化；通过HE染色、Elastin染色和免疫组织化学染色法观察各组小鼠组织结构的变化和炎症细胞浸润；通过细胞流式技术分析各组小鼠组织和血中炎症细胞的表达；通过PCR分析各组小鼠动脉壁内炎症因子表达水平；通过DHE染色确定主动脉壁内氧化应激的情况,通过免疫组织染色、Western Blot和明胶酶谱方法分析各组小鼠动脉壁内基质金属蛋白酶的表达及活性变化； (3)收集AAA病人及对照组血浆,通过ELISA方法检测不同组血浆中AGF表达水平,并分析不同直径腹主动脉瘤血浆AGF之间的差异。结果：1.Ang Ⅱ刺激诱导ApoE-/-小鼠建立成功诱导建立AAA动物模型；2.SB265610抑制CXCR2后显著抑制Ang Ⅱ诱导的ApoE-/-小鼠AAA形成(发生率及直径)；3. CXCR2被抑制后抑制Ang Ⅱ诱导的①动脉壁内巨噬细胞浸润；②基质金属蛋白酶的表达及活性；③氧化应激；4.腹主动脉瘤患者的血浆AGF水平升高,且直径较大的腹主动脉瘤升高程度更明显。结论：我们证明了CXCR2的激活可以促进腹主动脉瘤形成。其作用机制可能与血管紧张素Ⅱ诱导的巨噬细胞浸润,MMP表达和活性增加,氧化应激激活相关。CXCR2抑制剂SB265610可以抑制这些改变。而且,我们发现腹主动脉瘤患者的血浆AGF水平升高,且升高的程度可以反映腹主动脉瘤的大小。这些发现阐明了CXCR2参与AAA发生的病理生理学机制,为AAA治疗提供了一个新的治疗靶点；同时本研究还发现AGF在腹主动脉瘤患者血浆中的变化,有一定的诊断及随访价值。
[Abstract]:Background and objective: abdominal aortic aneurysm (AAA) is a common disease in aging society. Inflammation, degradation of extracellular matrix, apoptosis and phenotypic transformation of smooth muscle cells (SMC), and oxidative stress are the key links of AAA. Macrophage infiltration is the key to the progression of (AAA) in abdominal aortic aneurysms. Chemokine receptor CXCR2 and ligand play an important role in regulating macrophage infiltration in the tissues. However, during the progress of AAA, it is unclear how CXCR2 regulates macrophage infiltration and degrades extracellular matrix and causes oxidative stress. Therefore, SB265610, a specific inhibitor of CXCR2, was used to inhibit the expression of CXCR2, to clarify the regulatory effect of CXCR2 on the formation of AAA in mice, and to elucidate the specific molecular mechanism of CXCR2 promoting the progression of AAA. Secondly, plasma samples were collected from AAA patients and normal subjects to detect angiopoietin related growth factors and to explore the relationship between angiopoietin and the diameter of abdominal aortic aneurysms. Methods: (1) Animal AAA model was established by subcutaneous implantation of angiotensin 鈪，
本文编号：2420308
[Abstract]:Background and objective: abdominal aortic aneurysm (AAA) is a common disease in aging society. Inflammation, degradation of extracellular matrix, apoptosis and phenotypic transformation of smooth muscle cells (SMC), and oxidative stress are the key links of AAA. Macrophage infiltration is the key to the progression of (AAA) in abdominal aortic aneurysms. Chemokine receptor CXCR2 and ligand play an important role in regulating macrophage infiltration in the tissues. However, during the progress of AAA, it is unclear how CXCR2 regulates macrophage infiltration and degrades extracellular matrix and causes oxidative stress. Therefore, SB265610, a specific inhibitor of CXCR2, was used to inhibit the expression of CXCR2, to clarify the regulatory effect of CXCR2 on the formation of AAA in mice, and to elucidate the specific molecular mechanism of CXCR2 promoting the progression of AAA. Secondly, plasma samples were collected from AAA patients and normal subjects to detect angiopoietin related growth factors and to explore the relationship between angiopoietin and the diameter of abdominal aortic aneurysms. Methods: (1) Animal AAA model was established by subcutaneous implantation of angiotensin 鈪，
本文编号：2420308
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