Inflammation and Infection in Atherosclerosis

冠状动脉疾病(CAD)是世界范围内人类发病率和死亡率的主要原因。由于高胆固醇血症、吸烟和高血压等传统危险因素不能完全解释人群中冠心病的发病率，近年来人们对慢性感染性疾病如牙周感染等可能导致冠心病的研究产生了兴趣。流行病学研究表明，患有牙周感染的个体患冠心病的可能性要高出30%到100%；然而，仍然有可能是混杂因素导致了这些观察结果，而且缺乏解释这种联系的机制研究。牙周病与全身炎症状态有关，循环中的细胞因子和口腔病原体的一个可能靶点是血管内皮细胞，它在调节血管内稳态方面发挥着核心作用。由炎性细胞因子激活的内皮细胞促进了促动脉粥样硬化的表型，增加了炎症因子的表达，并丧失了内皮细胞的抗血栓、生长抑制和血管扩张特性。这些变化发生在动脉粥样硬化发展的早期，并有助于疾病的发病机制和临床表现。这项应用的目的是检验宿主炎症反应在感染加重的动脉粥样硬化中起主要作用的假设，并研究解释这一过程的特定信号机制。这项应用的具体目的是：目的1。确定动脉壁的系统性炎症与直接细菌侵入在动脉粥样硬化病变形成中的相对重要性。目的：确定抑制Toll样受体2(TLR2)和IL-1受体通路是否能抑制细菌攻击后动脉粥样硬化的形成。目的：探讨TLR2和IL-1受体通路激活是否加重动脉粥样硬化斑块形成。目的4：确定细菌性牙周炎小鼠模型是否会加重动脉粥样硬化。拟议的研究将为牙龈卟啉单胞菌如何促进动脉粥样硬化的形成和发展提供机械学上的见解。这一应用的长期目标是开发旨在控制动脉粥样硬化中炎症反应的有害影响的治疗策略。

DESCRIPTION: Coronary artery disease (CAD) is a major cause of morbidity and mortality in human worldwide. Recent interest has focused on chronic infectious diseases like periodontal infection as potential contributors to CAD since traditional risk factors like hypercholesterolemia, smoking and hypertension fail to fully explain the incidence of CAD in populations. Epidemiological studies indicate that individuals with periodontal infection are 30 to 100% more likely to have CAD; however, it remains possible that confounding factors account for these observations and mechanistic studies to explain this connection are lacking. Periodontal disease is associated with a state of systemic inflammation, and a likely target for circulating cytokines and oral pathogens is the vascular endothelium, which plays a central role in the regulation of vascular homeostasis. Activation of endothelial cells by inflammatory cytokines promotes a pro-atherogenic phenotype with increased expression of inflammatory factors and loss of the anti-thrombotic, growth inhibitory, and vasodilator properties of the endothelium. These changes occur early in the development of atherosclerosis and contribute to the pathogenesis and clinical expression of disease. The purpose of this application is to test the hypothesis that the host inflammatory response plays a primary role in infection-aggravated atherosclerosis and investigate the specific signaling mechanisms that account for this process. The Specific Aims of this application are: Aim 1. To determine the relative importance of systemic inflammation versus direct bacterial invasion of the arterial wall for atherosclerotic lesion formation. Aim 2: To determine whether inhibition of Toll-like Receptor 2 (TLR2) and IL-1 receptor pathways limits atherogenesis following bacterial challenge. Aim 3: To determine whether activation of TLR2 and IL-1 receptor pathways aggravate atherosclerotic plaque formation. Aim 4: To determine whether a mouse model of bacterial periodontitis exacerbates atherosclerosis. The proposed studies will provide mechanistic insights into how Porphyromonas gingivalis contributes to atherosclerosis formation and progression. The long-term goal of this application is to develop therapeutic strategies aimed at controlling the deleterious effects of the inflammatory response in atherosclerosis.