Inflammation and Infection in Atherosclerosis

冠状动脉疾病（CAD）是世界范围内人类发病和死亡的主要原因。由于传统的危险因素，如高胆固醇血症、吸烟和高血压不能完全解释冠心病在人群中的发病率，最近的兴趣集中在慢性感染性疾病，如牙周感染，作为CAD的潜在贡献者。流行病学研究表明，患有牙周感染的人患CAD的可能性高出30%至100%；然而，仍然有可能是混杂因素导致了这些观察结果，并且缺乏解释这种联系的机制研究。牙周病与全身性炎症状态有关，循环细胞因子和口腔病原体的一个可能靶点是血管内皮，它在血管稳态调节中起着核心作用。炎症细胞因子对内皮细胞的激活促进了促动脉粥样硬化表型，炎症因子的表达增加，内皮抗血栓、生长抑制和血管扩张特性的丧失。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。本应用的目的是验证宿主炎症反应在感染加重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。本应用程序的具体目标是：目标1。确定全身性炎症与直接细菌侵入动脉壁对动脉粥样硬化病变形成的相对重要性。目的2：确定toll样受体2 （TLR2）和IL-1受体途径的抑制是否限制了细菌攻击后动脉粥样硬化的发生。目的3：确定TLR2和IL-1受体通路的激活是否会加剧动脉粥样硬化斑块的形成。目的4：确定细菌性牙周炎小鼠模型是否会加剧动脉粥样硬化。提出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进展提供机制见解。这项应用的长期目标是制定治疗策略，旨在控制动脉粥样硬化中炎症反应的有害影响。

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.