【作者】 徐锦荣；

【导师】 丛斌；

【作者基本信息】 河北医科大学 ， 病理学与病理生理学， 2006， 博士

【摘要】 类风湿关节炎(rheumatoid arthritis RA)的主要病变在关节,在关节内可以看到滑膜组织异常增生、大量炎性细胞浸润以及软骨与骨进行性破坏,在关节外则表现为血管炎。疾病过程综合体现了滑膜组织增生、炎症、自身免疫这三种病理生理过程,它们之间相互作用、相互关联,形成了一个错综复杂的网络机制。成纤维样滑膜细胞(fibroblast-like synoviocytes,FLSs)是从RA滑膜中分离得到的外观类似成纤维细胞的一类滑膜细胞。目前认为,RA FLSs过度增生是造成滑膜增厚的主要原因。FLSs分泌IL-6、IL-8、粒-巨噬细胞集落刺激因子( granulocyte-macrophage colony-stimulating factor,GM-CSF)、前列腺素(prostaglandins,PGs)、基质金属蛋白酶(matrix metalloproteinases,MMPs)以及聚合素酶(aggrecanase)和组织蛋白酶等效应分子,对骨与软骨组织造成侵蚀,FLSs被认为是介导RA关节破坏的主要效应细胞,而TNF-α则是参与FLSs反应的关键性细胞因子。FLSs增殖和分泌在RA发病过程中发挥关键性作用。所以寻找具有调节FLSs上述功能的抗炎制剂已成为研究的热点。八肽胆囊收缩素(cholecystokinin octapeptide,CCK-8)是一种内源性脑肠肽,近年研究表明CCK-8具有抗炎和免疫调节作用。已有报道CCK-8对角叉菜胶诱导的大鼠关节炎有缓解作用。本室先前研究表明,CCK-8对TNF-α诱导胶原性关节炎(collagen-induced arthritis, CIA)大鼠滑膜细胞增殖及大鼠成纤维样滑膜细胞RSC-364增殖和MMP-2、MMP-9分泌皆有抑制作用,提示CCK-8对RA可能具有积极的药理作用。MMPs和MMPs组织抑制剂(tissue inhibitor of MMPs,TIMPs)系统失衡在RA软骨破坏中起关键作用。CCK-8对MMPs/ TIMPs系统有何影响,尚未见报道。调控MMPs表达及合成的信号转导机制极其复杂,它们往往同时参与RA其它炎性介质的合成及细胞增殖等过程。已知活化蛋白-1(activator protein-1, AP-1)是参与TNF-α诱导RA滑膜细胞MMPs基因表达、增殖及炎症反应的一个十分重要的转录因子。本室前期研究发更多还原

【Abstract】 Major pathological changes of rheumatoid arthritis (RA) exist in joint, characterized by hyperplasia of synovium, infiltration of abundant inflammatory cells and progressive destruction of cartilage and bone structures, while vasculitis appears outside of joint. Three pathophysiological changes of synovium hyperplasia, inflammation and autoimmunity are comprehensively personificated in the whole process of RA, which interact, correlate and form a reticular network running through pathogenesis of RA. Fibroblast-like synoviocytes (FLSs) isolated from synovium of RA play a major role in the pathogenesis of rheumatoid arthritis (RA) by uncontrolled proliferation and secreting effector molecules, including cytokines, chemokines, prostaglandins (PGs) and proteolytic enzymes such as matrix metalloproteinases (MMPs), aggrecanase and cathepsin, which promote inflammation and joint destruction. TNF-αhas been reported to be one of the important inflammatory mediators. Alterations in proliferation and secretion of FLSs are known to play a pivotal role in the development of RA. Therefore, agents which have regulatory action on FLSs proliferation and secretion might act as the potent therapeutic drugs for RA, and searching for these agents has become the focus in the study field of RA. Cholecystokinin-octapeptide (CCK-8) is a kind of endogenous brain-gut peptide. Recent studies suggest the anti-inflammatory and immunomodulatory effect of CCK-8. It has been reported that CCK-8 could protect adult rats from joint inflammation induced by carrageenan. Our previous study demonstrated that CCK-8 could inhibit proliferation of rat fibroblast-like synoviocyte line RSC-364 cells and collagen-induced arthritis (CIA) FLSs, and could induce a decrease in MMP-2 and -9 secretion in RSC-364 cells induced by TNF-α, indicating that CCK-8 might have an更多还原