本文選題：冠脈擴張 + 細胞外基質(zhì)�。� 參考：《北京協(xié)和醫(yī)學院》2015年博士論文

【摘要】：[研究背景]隨著冠脈影像學技術的普及,冠脈擴張(coronary artery ectasia, CAE)越來越多地被人們所認識,其發(fā)病率低但絕對人數(shù)多,且有類似于冠心病的臨床表現(xiàn),易于發(fā)生血栓事件,嚴重危害患者的健康和生命,然而目前缺乏對其針對性的治療措施,這主要是因為不清其確切的病因和發(fā)病機制。對冠脈擴張發(fā)病機制的深入研究,有助于科學地制定治療策略,從而緩解患者的臨床癥狀和改善長期預后。[研究目的]因為冠脈擴張?zhí)卣餍圆±肀憩F(xiàn)為冠脈中層細胞外基質(zhì)成分的嚴重損害,我們提出假設：做為機體細胞外基質(zhì)降解的最終執(zhí)行者,蛋白酶可能在冠脈擴張細胞外基質(zhì)的異常代謝過程中發(fā)揮著重要作用。本研究擬回答：1)冠脈擴張細胞外基質(zhì)代謝的特點如何?2)蛋白酶是否和冠脈擴張細胞外基質(zhì)的異常代謝相關?3)何種來源的蛋白酶參與了冠脈擴張的病程?4)哪些內(nèi)源性物質(zhì)能夠調(diào)控這些酶的作用?本研究期待明確蛋白酶與冠脈擴張的關系,為進一步的研究提供理論基礎。[研究方法]因為冠狀動脈管壁的主要細胞外基質(zhì)成分是彈力纖維、Ⅰ和Ⅲ型膠原纖維,本研究首先在血清中檢測這些細胞外基質(zhì)合成和降解的生物標志物,以初步評估冠脈擴張患者細胞外基質(zhì)代謝的總體情況,同時也研究了其中某些指標的臨床診斷價值。進而檢測血液中總彈性蛋白酶和總金屬基質(zhì)蛋白酶的活性變化,分析他們與冠脈擴張細胞外基質(zhì)代謝的相關性,在這個結(jié)果的指導下：1)進一步對中性粒細胞來源的蛋白酶及其內(nèi)源性抑制物做了系統(tǒng)的研究；2)系統(tǒng)篩查了冠脈擴張患者外周血單個核細胞(peripheral blood mononuclear cells, PBMC)相關蛋白酶及其調(diào)控分子轉(zhuǎn)錄表達譜；3)利用冠脈擴張混合血清模擬體內(nèi)的病理刺激,培養(yǎng)人臍靜脈平滑肌細胞,觀察其對蛋白酶表達和細胞外基質(zhì)代謝的影響,該部分還探討了細胞因子生長分化因子15 (growth differentiation factor 15, GDF-15)的保護作用。[研究結(jié)果]通過對膠原代謝指標系統(tǒng)檢測發(fā)現(xiàn)：冠脈擴張患者彈性纖維降解增多,總膠原量減少,膠原極性由Ⅲ型為主向Ⅰ型為主轉(zhuǎn)化。這些變化可能與冠狀動脈擴張的形成,以及血管的硬化有密切的聯(lián)系。進一步研究發(fā)現(xiàn),總彈性蛋白酶和總金屬質(zhì)蛋白酶(matrix metalloproteinase, MMP)與彈力纖維降解密切相關。其中彈性纖維的降解產(chǎn)物——可溶性彈力蛋白(soluble elastin, sElastin)有助于冠脈擴張的輔助診斷。在這個基礎上開展的實驗顯示：1)冠脈擴張組的中性粒細胞以一種未知的方式激活,釋放出中性粒細胞彈性蛋白酶(human neutrophil elastase, HNE)和組織蛋白酶G (cathepsin G, CG),同時內(nèi)源性蛋白酶抑制物相應升高來限制它們的過度破壞作用,但這些蛋白酶抑制物同時也抑制了纖溶酶,影響了纖溶系統(tǒng)的功能,理論上增加了冠脈擴張血栓事件的概率。2)系統(tǒng)篩查單個核細胞的蛋白酶及其調(diào)控體系的表達譜發(fā)現(xiàn),單個核細胞來源的金屬基質(zhì)蛋白酶MMP1和MMP9,以及單個核細胞來源的細胞因子白細胞介素1α (interleukin-1A, IL1A)、血小板衍化生長因子B(Platelet-derived growth factor B, PDGF-B)、干擾素γ(Interferon gamma, IFNγ)和GDF15,可能都參與到冠脈擴張的疾病進程。3)冠脈擴張混合血清能上調(diào)人臍靜脈平滑肌細胞MMP1的表達,加入GDF-15后這種上調(diào)高能夠被抑制,提示GDF-15是可能是一種內(nèi)源保護性因子。[研究結(jié)論]本研究以細胞外基質(zhì)代謝和蛋白酶解作用為中心開展了一系列的實驗,進一步證實冠脈擴張的主要機制是彈力纖維的破壞和膠原總量的減少,其中可溶性彈力蛋白sElastin有望新的輔助診斷指標；參與冠脈擴張的蛋白酶主要有：平滑肌細胞來源的MMP1,單個核細胞來源的MMP1和9,中性粒細胞來源的HNE和CG,同時機體還有一系列內(nèi)源性的物質(zhì)來調(diào)控蛋白酶的作用,包括數(shù)個蛋白酶抑制物和數(shù)個細胞因子,其中GDF15有潛力成為治療冠脈擴張的一種藥物。本研究初步證實了蛋白酶與冠脈擴張的密切關系,為后續(xù)的深入研究提供了理論基礎。
[Abstract]:[background] with the popularization of coronary imaging technology, coronary artery ectasia (CAE) is becoming more and more recognized by people. The incidence of coronary artery disease is low but the absolute number is large, and there are similar clinical manifestations of coronary heart disease. It is easy to have thrombus events and seriously harm the health and life of the patients. However, there is no pertinence to it at present. This is mainly due to the lack of clear etiology and pathogenesis. An in-depth study of the pathogenesis of coronary dilatation helps to scientifically formulate therapeutic strategies to alleviate the clinical symptoms and to improve the long-term prognosis. [Objective] the characteristic pathological manifestations of coronary dilatation are the components of the extracellular matrix of the middle layer of coronary artery. Serious damage, we propose that as the ultimate performer for the degradation of the extracellular matrix of the body, protease may play an important role in the abnormal metabolic process of the extracellular matrix of coronary dilatation. This study is intended to answer: 1) what are the characteristics of the extracellular matrix metabolism in coronary dilatation? 2) whether the protease is extended to the extracellular matrix of the coronary artery Abnormal metabolism related? 3) what is the source of protease involved in the course of coronary dilatation? 4) what endogenous substances can regulate the role of these enzymes? This study expects to clarify the relationship between protease and coronary dilatation and provide a theoretical basis for further research. [research methods] the main extracellular matrix component of the coronary artery wall is a projectile Force fibers, type I and type III collagen fibers. This study first examined the biomarkers of these extracellular matrix synthesis and degradation in serum to evaluate the overall status of the extracellular matrix metabolism in patients with coronary dilatation, and also to study the clinical diagnostic value of some of these indicators. Then, the total elastase and total gold in the blood were detected. The changes in the activity of matrix protease, analysis of their correlation with the metabolism of extracellular matrix of coronary dilatation, under the guidance of this result: 1) further study of neutrophil derived protease and its endogenous inhibitors; 2) systematic screening of peripheral blood mononuclear cells (peripheral blood Mo) in patients with coronary dilatation Nonuclear cells, PBMC) related proteases and their regulatory molecular transcriptional expression profiles; 3) the effects of cultured human umbilical vein smooth muscle cells on the expression of protease and the metabolism of extracellular matrix were observed by using coronary dilatation mixed serum to simulate the pathological stimulation in vivo, and the cytokine growth differentiation factor 15 (growth different) was also discussed. The protective effect of iation factor 15, GDF-15). [results] through the examination of the collagen metabolism index system, it was found that the degradation of elastic fibers in the patients with coronary artery dilatation was increased, the total amount of collagen was reduced, and the collagen polarity was mainly converted from type I to type I. These changes may be associated with the formation of coronary artery dilation and the hardening of blood vessels. Further studies have found that the total elastase and the total metal proteinase (matrix metalloproteinase, MMP) are closely related to the degradation of elastic fibers. The degradation products of the elastic fibers, soluble elastin (soluble elastin, sElastin), are helpful for the auxiliary diagnosis of coronary dilatation. 1) the neutrophils in the coronary dilatation group are activated in an unknown manner, releasing human neutrophil elastase (HNE) and cathepsin G (cathepsin G, CG), while endogenous protease inhibitors increase accordingly to limit their overdestruction, but these inhibitors also inhibit the activity of these protease inhibitors. Plasminase, which affects the function of fibrinolytic system, theoretically increases the probability of coronary dilatation thrombosis (.2), the expression profiles of the protease and its regulatory system of mononuclear cells, the metal matrix protease MMP1 and MMP9 from mononuclear cells, and the cytokine interleukin 1 alpha (Interl) from the single nuclear cell source. Eukin-1A, IL1A), platelet derived growth factor B (Platelet-derived growth factor B, PDGF-B), interferon gamma (Interferon gamma, IFN gamma) and GDF15, may be involved in the progression of coronary dilatation. It is suggested that GDF-15 is probably an endogenous protective factor. [Conclusion] this study conducted a series of experiments centered on extracellular matrix metabolism and proteolysis, and further confirmed that the main mechanism of coronary dilatation is the destruction of elastic fibers and the decrease of total collagen, in which the soluble elastin sElastin is expected to be new. The protease involved in coronary dilatation mainly include MMP1 of smooth muscle cells, MMP1 and 9 of mononuclear cells, HNE and CG derived from neutrophils, and a series of endogenous substances that regulate the role of protease, including several protease inhibitors and several cytokines, of which GDF15 has potential. Force has become a drug for the treatment of coronary dilatation. This study has preliminarily confirmed the close relationship between protease and coronary dilatation, which provides a theoretical basis for further further research.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R541.4

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