【作者】 郭涛；

【导师】 张运；

【作者基本信息】 山东大学 ， 内科学， 2006， 博士

【摘要】 背景 冠心病和脑卒中是严重危害人类健康的常见病和多发病，其病理基础是动脉粥样硬化(AS)。大量证据表明，在AS的形成和发展过程中，内皮细胞、平滑肌细胞、巨噬细胞、T淋巴细胞、肥大细胞等发挥了重要的作用。晚近的研究证实肥大细胞与AS的发生发展密切相关。肥大细胞通过分泌多种炎症介质，包括糜酶(chymase)、组胺和各种化学因子及细胞因子，诱导血管炎症反应、内皮功能失调、泡沫细胞形成、胞外基质降解和微血管新生等，对AS斑块的形成及斑块稳定性起着重要作用。其中，肥大细胞分泌的糜酶与AS病程进展关系尤为密切。综合研究表明，糜酶可能通过以下途径促进AS的形成和发展过程：(1)通过介导非经典途径激活血管组织中的肾素—血管紧张素系统(RAS)，引起血管紧张素Ⅱ(Ang Ⅱ)生成增加，促进AS病变的进展和斑块易损；(2)通过水解活化多种炎性因子，促进AS的炎症反应过程，加速AS的进展；(3)通过降解载脂蛋白AI(Apo-AI)，阻碍泡沫细胞的胆固醇外向转运，引起胞内脂质淤积，导致细胞坏死脂质沉积，促进AS斑块的形成和发展；(4)直接蛋白水解斑块纤维帽的基质成分，如：连接蛋白、层粘连蛋白、弹性蛋白、Ⅳ型和Ⅴ型胶原，导致纤维帽变薄，促进斑块向不稳定方向转变；(5)通过活化基质金属蛋白酶-1(MMP-1)、MMP-2、MMP-3和MMP-9，导致斑块纤维帽的基质成分水解而影响斑块的稳定性；(6)通过活化多种炎性因子诱导斑块血管平滑肌细胞(VSMC)凋亡并抑制其分泌活性，促进斑块纤维帽变薄，降低斑块稳定性等；(7)通过促进Ang Ⅱ及内皮素—1(ET-1)等递质的分泌，增加血管病变局部的血流剪切力，促进AS斑块向不稳定方向发展。总之，糜酶在AS的发生和发展过程中发挥着更多还原

【Abstract】 BackgroudAcute cardiovascular disease and cerebrovascular disease are two common and multi-onset diseases, which have serious effects on the health of human beings, and their pathological basis is atherosclerosis (AS) .Extensive evidence supports that endotheliocyte, smooth muscle cells, macrophages , T lymphocyte and mast cells play a vital role in the development of atherosclerosis. Recent studies show that mast cells have a close relationship with atherosclerosis due to their secretion of inflammmatory factors such as chymase, histamine and other cytokines. Research shows that chymase prompts development of atherosclerosis through the following ways: (1) Increasing Ang II forming of vascular tissues by activating renin -angiotensin system (RAS), which prompts atherosclerosis development.(2) Accelerating atherosclerotic plaques development by activating inflammatory factors of atherosclerosis process; (3)Accelerating atherosclerotic plaques development by degradating apolipoprotein AI, which prevents foam cells from extraversing cholesterol. (4) Prompting plaque unstable by directly proteolyzing matrix ingredient of plaque cap such as connective protein, laminin , resilin, collogen IV and V, which causes caps of plaque thinner.(5)Making the plaque cap thinner by activating MMP-1, MMP-2, MMP-3, and MMP-9 and causing the plaque vulnerability.(6)Exerting a destabilizing effect on the plaque by inducing vascular smooth muscle cells(VSMCs)apoptosis and inhibiting VSMCs secretion by degradating fibronectin and activating inflammatory factors. (7) Augmenting shear stress acting on the arterial wall through many ways, which causes更多还原