炎症反应在易损斑块中的作用及其机制研究进展

炎症反应在易损斑块的形成和进展中发挥重要作用,同时调控血管局部病变及全身炎症状态。一些促炎性细胞和炎症因子使斑块纤维帽的抗张强度降低,坏死脂质内核增大,血管机械稳定性丧失和斑块破裂;另一方面,炎症反应的激活和代谢紊乱也会引起内皮功能不全、斑块侵蚀进而导致血栓形成。该过程主要由巨噬细胞和淋巴细胞等多种炎症细胞参与,并受到多种因素调控,包括胆固醇结晶和脂质递质、血管剪切力、血管新生及斑块内出血等。此外,机体还存在一些抑炎性分子,能避免易损斑块向破裂或侵蚀进展。促炎和抗炎反应的平衡影响急性冠状动脉事件的发生。因此,以炎症反应为靶点,筛选出有易损斑块的患者并干预,或可减少急性冠状动脉事件的发生和改善预后,具有重要临床价值。     

易损斑块的血清标记物研究进展

临床研究证实炎症在动脉粥样硬化损伤的各阶段均有重要作用,包括从脂纹形成到最终易损斑块的破裂。炎症标记物可以反映与急性冠状动脉综合征的各个阶段相关联的动脉粥样硬化进程的不同侧面,还可能与急性冠状动脉综合征的严重性有关。该综述总结了有关炎症标记物的文献,为使用炎症标记物检测易损斑块的可行性提供了一些证据。这些证据可能会促使动脉粥样硬化患者的管理更加完善,包括一级预防和二级预防。     

动脉粥样硬化易损斑块的生物学标志物

多种生化分子参与了动脉粥样硬化的发生发展、斑块失稳定性和破裂过程.因此,寻找能识别易损斑块和预测斑块破裂风险的血清生物学标志物,对临床工作具有重要的指导意义.文章综述了近年来有关易损斑块生物学标志物的研究进展.     

动脉粥样硬化易损斑块的生物学标志物

多种生化分子参与了动脉粥样硬化的发生发展、斑块失稳定性和破裂过程.因此,寻找能识别易损斑块和预测斑块破裂风险的血清生物学标志物,对临床工作具有重要的指导意义.文章综述了近年来有关易损斑块生物学标志物的研究进展.     

易损斑块的血清炎症标志物的研究进展

急性冠状动脉综合征是严重威胁人类健康的一种常见病和多发病。急性冠状动脉综合征的病理基础是由于易损斑块的存在,且易损斑块的破裂是急性冠状动脉综合征发生的始动环节。现有临床检测方法仅能监测到急性冠脉事件发生的当时及事后血清学变化,而早期发现易损斑块,及时进行干预,对降低急性冠状动脉综合征的发病率和死亡率具有极其重要的临床意义。现主要就检测易损斑块的血清炎症标志物的研究进展作一综述。     

炎症标志物与急性冠状动脉综合征

动脉粥样硬化性疾病是一种慢性、非特异性、炎性疾病。在动脉粥样硬化性疾病的不同临床表现过程中,炎症与其发生和发展的所有阶段有关。急性冠状动脉综合征是冠心病的特殊疾病谱,新近研究证实,炎症在急性冠状动脉综合征患者的粥样斑块破裂与血栓形成中起主要作用。炎症与易损斑块的形成有关;临床试验证据支持炎症在急性冠状动脉综合征发生中的病因学地位;炎症标志物的使用,也提供了一个了解急性冠状动脉综合征病理生理机制的窗口。因此,急性冠状动脉综合征可以认为是一种心血管急性炎症综合征。     

预测冠状动脉易损斑块新的炎症标志物:脂蛋白相关磷脂酶A_2

急性冠状动脉综合征主要由易损斑块引发血栓形成,导致急性心肌梗死,其罪犯病变的突出特征包括薄纤维帽破裂、巨大的富含脂质坏死核心和大量的炎症细胞浸润.     

���Թ�״�����ۺ����ķ�������

近年的研究证明,斑块破裂、血小板聚集及血栓形成是急性冠状动脉综合征(ACS)的主要发病机制,其中斑块破裂是ACS发生中最重要的始动环节。随着动物实验和临床研究的进一步深入,易损斑块发生、发展的分子生物学机制研究方面已取得很大进展。近年来国内外学者主要应用载脂蛋白E基因缺陷(ApoE-/-)小鼠以及球囊损伤血管内皮加高胆固醇饲养并野生型p53基因转染的新西兰兔作为易损斑块动物模型,进行易损斑块的分子生物学研究,发现炎症反应是动脉粥样硬化(AS)的核心因素。1炎症与斑块易损性在ACS死亡病例尸检中发现冠状动脉斑块中存在泡沫细胞…     

动脉粥样硬化易损斑块的动物模型和检测技术

动脉粥样硬化易损斑块破裂、血栓形成是急性冠状动脉综合征的发病机制已成为共识。由于缺乏理想的易损斑块的动物模型,对斑块破裂前的血清学及影像学特征研究较少,尚缺乏能够早期识别易损斑块及预防斑块破裂的最佳方法。本实验室已成功构建家兔和Apo E-/-小鼠的易损斑块模型。易损斑块的检测技术主要包括非侵入性及侵入性的影像学检测及功能学检测技术。对易损斑块的早期准确识别以便及时干预具有十分重要的临床意义。     

麝香通心滴丸对稳定动脉粥样硬化斑块的机制研究

目的观察麝香通心滴丸稳定动脉粥样硬化(AS)斑块的作用机制。方法采用高脂饮食伴主动脉内膜球囊损伤复制家兔动脉粥样硬化斑块模型,药物(斑点蝰蛇毒、组胺)触发斑块破裂,观察麝香通心滴丸稳定易损斑块的作用机制。生化方法检测AS家兔的血脂及氧化应激水平;ELISA及实时荧光定量PCR(Real-Time RT-PCR)法检测麝香通心滴丸对AS家兔基质金属蛋白酶-2(MMP-2)、TIMP2以及相关炎症介质的蛋白含量和mRNA表达水平的影响;应用TUNEL法检测麝香通心滴丸对AS家兔斑块内细胞凋亡水平的影响。结论麝香通心滴丸稳定易损斑块作用的机制有,减轻AS氧化应激损伤,降低脂质过氧化;降低MMP2含量,升高TIMP2含量,减少AS斑块内的基质降解,调节基质代谢;减少斑块内巨噬细胞的数量,降低炎性因子的表达,减轻斑块内的炎症反应;减少斑块内细胞凋亡增加斑块稳定性。     

Biomarkers of atherosclerotic plaque instability and rupture

Basic research over the last two decades has identified a large number of molecules pertinent to the atherosclerotic process, which have clearly improved our understanding of the underlying pathology. It is now well established that inflammation represents a major feature which is present in the vessel wall throughout all stages of the disease until the final pathophysiologic steps, representing plaque destabilization and eventually plaque rupture. Several cells typical for the atherosclerotic plaque, like monocyte-derived macrophages and T-lymphocytes are able to produce and secrete such mediator molecules, like cytokines, chemokines, growth-factors, enzymes, and disintegrins, which lead to activation of endothelial cells, proliferation of smooth muscle cells, lesion progression, and finally to the weakening of a vulnerable plaque by matrix degradation of its fibrous cap. Today, many of these molecules involved can be measured systemically by sensitive assays, and elevated concentrations in the circulation have been shown to be associated with future cardiovascular events. Determination of several of these molecules carries important prognostic information, independent of traditional risk factors, and may turn out to be useful in improving risk stratification. However, for most of these biomarkers the clinical utility has not yet been established.     

CDl63／HO-1通路激活在稳定动脉粥样硬化斑块中的作用

动脉粥样硬化（atherosclerosis，AS）目前被广泛认为是一种慢性炎症性疾病，炎症反应与斑块的不稳定性密切相关。CD163作为血红蛋白特异清道夫受体，近年被研究发现可以调节血红素氧合酶-1（hemeoxygenase-1，HO-1）的表达，而后者已经大量实验证明具有抗炎、抗氧化作用。因此有学者提出，CD163／HO-1通路作为一个新的抗炎途径，有望在稳定动脉粥样硬化不稳定斑块中起着重要作用。     

CD163/HO-1通路激活在稳定动脉粥样硬化斑块中的作用

动脉粥样硬化(atherosc lerosis,AS)目前被广泛认为是一种慢性炎症性疾病,炎症反应与斑块的不稳定性密切相关。CD163作为血红蛋白特异清道夫受体,近年被研究发现可以调节血红素氧合酶-1(hem e oxygenase-1,HO-1)的表达,而后者已经大量实验证明具有抗炎、抗氧化作用。因此有学者提出,CD163/HO-1通路作为一个新的抗炎途径,有望在稳定动脉粥样硬化不稳定斑块中起着重要作用。     

Evolving Concepts in the Triad of Atherosclerosis,Inflammation and Thrombosis

Recent developments into antherothrombosis, the leading cause of morbidity and mortality in Western Society, may help to change our treatment strategy to a more casual approach. The composition of the atherosclerotic plaque, rather than the percent stenosis, appears to be a critical predictor for both risk of plaque rupture and subsequent thrombogenicity. A large lipid core, rich in tissue factor (TF) and inflammatory cells including macrophages, and a thin fibrous cap with compromise of its structural integrity by matrix degrading enzymes, such as metalloproteinases (MMPs), render a lesion susceptible to rupture and subsequent acute thrombosis. Thrombosis may lead to a complete occlusion or, in the case of mural thrombus or intraplaque hemorrhage, to plaque progression. Disruption of a vulnerable or unstable plaque (type IV and Va lesions of the AHA classification) with a subsequent change in plaque geometry and thrombosis may result in an acute coronary syndrome. The high-risk plaque tend to be relatively small, but soft or vulnerable to "passive" disruption because of high lipid content. Inflammatory processes are important components of all stages of atherosclerotic development, including plaque initiation and disruption. As such the early steps in atherosclerotic lesion formation are the over expression of endothelial adhesive protein (i.e. selectins, VCAM and ICAM), chemotactic factors (MCP-1), growth factors (M-CSF), and cytokines (IL-2) that will facilitate the recruitment, internalization and survival of blood-borne inflammatory cells into the vascular wall. Macrophages, following what appears to be a defense mission by protecting the vessel wall from excess lipid accumulation, may eventually undergo apoptosis with release of MMPs and TF. Specific cell recruitment in the vessel wall and build-up of the extracellular matrix are coordinated by a wide variety of stimulators and inhibitors. Active interaction of immune competent cells within the atherosclerotic lesions appears to play a pivotal role in the control of atherosclerotic plaque evolution and, therefore, deserves particular attention from the research community with the ultimate goal of improving preventive and therapeutic medical approaches. Inflammation, thrombosis and atherosclerosis are interdependent and define a triad within the complex pathogenic process of atherothrombosis.     

Significance of peptidoglycan,a proinflammatory bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques

Peptidoglycan (PG) is a major component of the cell wall of gram-positive bacteria that is abundantly present in all human mucosa. PG is a functional lipopolysaccharide analog that binds to CD14 on macrophages and induces proinflammatory cytokine production and metalloproteinases. We investigated the hypothesis that bacterial PG is present in atherosclerotic tissue. In addition, plaque phenotypes were characterized in relation to presence of PG. Immunohistology of carotid (n = 15) and femoral (n = 6) endarterectomy specimens revealed the presence of PG in the cytoplasm of cells located in plaques. PG was detected in 14 of 15 carotid arteries and 5 of 6 femoral arteries. From the 14 coronary arteries, 31 atherosclerotic segments were selected. PG was detected within 19 of 31 of these coronary segments. Western blot demonstrated the presence of the toll-like receptor (TLR-2), the co-receptor for PG, in coronary artery tissue. The number of PG-containing cells in coronary arteries was significantly higher when the histologic features of plaque vulnerability were evident. Inflammation of the cap or shoulder was observed in 11 of 19 PG-positive versus 2 of 12 PG-negative segments (p = 0.023). More than 50% of the plaque area consisted of atheroma in 7 of 19 PG-positive segments and 0 of 12 PG-negative segments (p = 0.025). Heavy smooth muscle cell staining occurred in the plaque cap and shoulder in 3 of 19 PG-positive segments versus 9 of 12 PG-negative segments. Proinflammatory bacterial PG and its co-receptor have been observed in atherosclerotic arteries, in association with the vulnerable plaque phenotype.     

Tissue factor expression in the morphologic spectrum of vulnerable atherosclerotic plaques

Inflammation and thrombosis are key events in the long-lasting sequence of atherosclerotic plaque initiation, plaque growth, and eventual onset of complications leading to clinically manifest disease. Recent cellular and molecular studies have indicated that inside the plaque tissue complex, proinflammatory and prothrombotic mechanisms are intimately associated, and tissue factor (TF) is one of the main proteins that may link both processes. It is therefore not surprising that TF expression appeared to be a prominent feature in various types of vulnerable atherosclerotic plaques (i.e., lesions that specifically predispose to the onset of symptomatic atherosclerotic disease).     

Atherosclerotic plaque burden,plaque vulnerability and arterial remodeling: the role of inflammation

Atherosclerotic narrowing of the arterial lumen is caused by gradual plaque growth and arterial remodeling. Expansive remodeling retards and constrictive remodeling accelerates narrowing of the lumen by plaque accumulation. In the acute phase luminal narrowing may be accelerated by rupture of a vulnerable plaque and subsequent thrombus formation. Inflammatory cells are key players in all these determinants of atherosclerotic luminal narrowing. Inflammatory cells are present in both early and advanced stages of atherosclerosis. Chronic infections have been suggested as trigger of arterial inflammation, but no causal relationship has yet been proved. Systemic markers of inflammation, like C-reactive protein, are predictors for the occurrence of future adverse cardiovascular events, confirming the role of inflammatory responses in arterial occlusive disease. In this review the central role of inflammation in atherosclerotic luminal narrowing will be discussed.     

胰岛素样生长因子结合蛋白-4作为动脉粥样硬化易损斑块标志物的研究进展

动脉易损斑块是导致主要不良心血管事件(MACEs)的重要危险因素,对易损斑块的早期准确评估及有效干预具有重要的临床意义。胰岛素样生长因子结合蛋白-4(IGFBP-4)是妊娠相关蛋白-A(PAPP-A)在易损斑块中水解的底物,可介导局部胰岛素样生长因子(IGF)释放,加速动脉粥样硬化斑块的进展,是易损斑块重要的生物标志物之一。易损斑块是急性冠脉综合征(ACS)的病理基础,是目前心血管领域的研究热点,本文综述了IGFBP-4在易损斑块发生发展中的作用及其判断易损斑块和预测MACEs的潜在作用。     

Biomarkers of Plaque Instability

Atherosclerosis is the proximate cause of arterial thrombosis, leading to acute occlusive cardiovascular syndromes. Thrombosis in atherosclerosis usually results from rupture of the fibrous cap of atherosclerotic plaques with a smaller proportion resulting from superficial endothelial erosion. Ruptured plaques are often associated with intimal and adventitial inflammation, increased size of lipid-rich necrotic core with thinned out collagen-depleted fibrous cap, outward remodeling, increased plaque neovascularity, intraplaque hemorrhage, and microcalcification. By inference, non-ruptured plaques with similar compositional features are considered to be at risk for rupture and hence are labeled vulnerable plaques or high-risk plaques. Identification of vulnerable plaques may help in predicting the risk of acute occlusive syndromes and may also allow targeting for aggressive systemic and possibly local therapies. Plaque rupture is believed to result from extracellular matrix (which comprises the protective fibrous cap) dysregulation due to excessive proteolysis in the context of diminished matrix synthesis. Inflammation is believed to play a key role by providing matrix-degrading metalloproteinases and also by inducing death of matrix-synthesizing smooth muscle cells. Systemic markers of inflammation are thus the most logical forms of potential biomarkers which may predict the presence of vulnerable or high-risk plaques. Several studies have suggested the potential prognostic value of a variety of systemic markers, but regrettably, their overall clinical predictive value is modestly incremental at best, especially for individual subjects compared to groups of patients. Nevertheless, continued investigation of reliable, cost-effective biomarkers that predict the presence of a high-risk plaque and future athero-thrombotic cardiovascular events with greater sensitivity and specificity is warranted.