Project 3: Diesel Exhaust, Vascular Response & Systemic Inflammation

项目 3：柴油机尾气，血管反应

• 批准号: 8278531
• 负责人: Stephan Van Eeden
• 金额: $ 30.02万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278531
• 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.

与交通有关的空气污染与心脏病恶化有关，具体来说，它会引发 因心脏病发作、心律不齐、心力衰竭发作和心脏病死亡而入院 疾病柴油机排气颗粒物（DEP）是城市交通相关大气污染物的重要组成部分。的 本研究的总体目标是确定DEP暴露对血管的影响。我们广泛 假设空气污染物影响血管，导致不利的心血管健康影响。我们 建议使用成熟的老年Apo-E基因敲除小鼠暴露于DEP的模型， 动脉粥样硬化是导致心脏病发作和中风的潜在疾病。该模型 代表流行病学研究显示有可能受到空气污染不良影响的受试者， 即具有预先存在的动脉粥样硬化的老年受试者。我们会致力达致以下的具体目标： DEP暴露后血管反应的功能研究。这些研究涉及 从暴露于DEP 7周的小鼠中收获主动脉，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 在血管内皮细胞中激活，可能参与异常的功能反应， 暴露于DEP后的血管。3)循环促炎介质的测量 包括急性期蛋白、细胞因子和白细胞以及血管活性介质如一氧化氮 以及与暴露于空气污染后的异常血管反应有关的内皮素。四、 定量组织学研究，以量化DEP暴露诱导的肺部炎症以及 肺中的颗粒负荷，并将这些与血管的下游异常血管反应相关。 许多流行病学研究表明，暴露于空气污染颗粒物对 心脏和血管。吸入颗粒物进入肺部影响血管的机制， 这一点并不明确，也是本次提案的重点。这项研究将推进我们的见解，在如何沉积罚款 肺中的颗粒导致不利的健康影响，例如触发心绞痛、心脏病发作或中风。 了解这些机制有助于确定哪些潜在的治疗干预可以 防止空气污染物对心脏和血管的不良健康影响。