Project 3: Diesel Exhaust, Vascular Response & Systemic Inflammation

项目 3：柴油机尾气，血管反应

• 批准号: 8376274
• 负责人: Stephan Van Eeden
• 金额: $ 30.74万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376274
• 关键词: Acute-Phase Proteins; Admission activity; Adverse effects; Agonist; Air Pollutants; Air Pollution; Aorta; Apolipoprotein E; Atherosclerosis; Blood Vessels; Breathing; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Deposition; Diesel Exhaust; Disease; Endothelin; Endothelium; Epidemiologic Studies; Exposure to; Harvest; Health; Heart; Heart Diseases; Heart failure; Hospitals; Inflammation; Inflammation Mediators; Knockout Mice; Leukocytes; Lung; Lung Inflammation; Measurement; Measures; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Nitric Oxide; Particulate Matter; Pathway interactions; Research; Risk; Stroke; Therapeutic Intervention; cytokine; heart rhythm; insight; mortality; particle; particle exposure; prevent; response; trafficking

Traffic related air pollution has been associated with exacerbation of heart disease, specifically, it triggers hospital admissions for heart attacks, irregular heart rhythms, episodes of heart failure and deaths from heart disease. Diesel exhaust particles (DEP) is an important component of urban traffic related air pollutants. The overall objective of this study is to determine the effects of DEP exposure on blood vessels. Our broad hypothesize is that air pollutants impact blood vessels resulting in adverse cardiovascular health effects. We propose to use as well established model of DEP exposure of older Apo-E knock-out mice, mice that naturally develop atherosclerosis, the underlying disease resulting in heart attacks and stroke. This model represents subjects at risk for the adverse effects of air pollution as shown in epidemiological studies, namely older subjects with pre-existing atherosclerosis. We will pursue the following specific aims: 1) Functional studies on the responses of blood vessels following DEP exposure. These studies involved harvesting the aorta from mice exposed to DEP for 7 weeks and expose these vessels to different agonist and antagonist, measuring the ability of vessels to constrict and dilate. 2) Determine the different pathways activated in the endothelium of blood vessels that could be involved in the abnormal functional response of blood vessels following DEP exposure. 3) Measurement of circulating pro-inflammatory mediators that in include acute phase proteins, cytokines and leukocytes as well as vasoactive mediators such as Nitric Oxide and endothelins that has been implicated in abnormal vascular responses following air pollution exposure. 4) Quantitative histological studies to quantify the lung inflammation induced by DEP exposure as well as the particle burden in the lung and relate these to the downstream abnormal vascular response of blood vessels. Numerous epidemiological studies have implicated exposure to air pollution particles to adverse effects on the heart and blood vessels. The mechanisms how inhalation of particles into the lung impact blood vessels, are unclear and is the focus of this proposal. This research will advance our insights in how deposition of fine particles in the lung results in adverse health effects such as triggering angina, a heart attack or stroke. Understanding these mechanisms could help to determine what potential therapeutic intervention could prevent the adverse health effects of air pollutants on the heart and blood vessels.

与交通相关的空气污染与心脏病的加剧有关，特别是它触发了 心脏病发作，不规则心律，心力衰竭情节和死亡的医院入院 疾病。柴油排气颗粒（DEP）是城市交通相关的空气污染物的重要组成部分。这 这项研究的总体目的是确定DEP暴露对血管的影响。我们的广阔 假设的是，空气污染物会影响血管，导致心血管健康影响不良。我们 建议使用较老的apo-e敲除小鼠的Dep暴露模型，该模型是小鼠 自然会发展动脉粥样硬化，这是潜在的疾病，导致心脏病发作和中风。这个模型 如流行病学研究所示，代表空气污染不利影响的受试者， 即具有预先存在动脉粥样硬化的老年受试者。我们将追求以下具体目标：1） DEP暴露后血管反应的功能研究。这些研究涉及 从暴露于DEP的小鼠中收集主动脉7周，并将这些血管暴露于不同的激动剂 和拮抗剂，测量血管收缩和扩张的能力。 2）确定不同的途径 在血管内皮中激活，可能参与 Dep暴露后的血管。 3）测量在 包括急性相蛋白，细胞因子和白细胞以及血管活性介质（例如一氧化氮） 在空气污染暴露后与异常血管反应有关的内皮蛋白。 4） 定量组织学研究，以量化DEP暴露引起的肺部炎症以及 肺中的颗粒负担与血管下游异常血管反应有关。 许多流行病学研究已暗示暴露于空气污染颗粒对不利影响 心脏和血管。该机制如何吸入颗粒进入肺部，影响血管， 不清楚，是该提议的重点。这项研究将提高我们对罚款表现的见解 肺中的颗粒会导致不良的健康作用，例如触发心绞痛，心脏病发作或中风。 了解这些机制可以帮助确定哪些潜在的治疗干预措施可以 防止空气污染物对心脏和血管的不利影响。