Inflammation and Infection in Atherosclerosis

描述：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。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，因为传统的风险因素，如高胆固醇血症，吸烟和高血压不能完全解释人群中CAD的发病率。流行病学研究表明，牙周感染的个体患CAD的可能性增加30%至100%;然而，仍然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相关，循环细胞因子和口腔病原体的可能靶点是血管内皮，其在血管稳态调节中起核心作用。通过炎性细胞因子激活内皮细胞促进促动脉粥样硬化表型，同时增加炎性因子的表达和内皮的抗血栓形成、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。本申请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，并研究解释该过程的特定信号传导机制。本申请的具体目标是：目标1。确定全身性炎症与动脉壁直接细菌侵入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受体通路的抑制是否限制了细菌攻击后的动脉粥样硬化形成。目的3：探讨TLR2和IL-1受体通路的激活是否加重动脉粥样硬化斑块的形成。目的4：确定小鼠细菌性牙周炎模型是否加重动脉粥样硬化。拟议的研究将提供牙龈卟啉单胞菌如何有助于动脉粥样硬化的形成和进展的机制的见解。本申请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作用的治疗策略。

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.