Project 3: Diesel Exhaust, Vascular Response & Systemic Inflammation

项目 3：柴油机尾气，血管反应

• 批准号: 7848223
• 负责人: Stephan Van Eeden
• 金额: $ 30.38万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7848223
• 关键词: Acute; Acute-Phase Proteins; Adherence; Admission activity; Adverse effects; Agonist; Air Pollutants; Air Pollution; Aorta; Apolipoprotein E; Atherosclerosis; Attenuated; Biological Availability; Blood Platelets; Blood Vessels; Bone Marrow; Breathing; Breeding; Calcium; Cardiovascular Diseases; Cardiovascular system; Ceruloplasmin; Cessation of life; Chronic; Data; Deposition; Development; Diabetes Mellitus; Diesel Exhaust; Disease; Doxycycline; Endothelial Cells; Endothelin; Endothelin-1; Endothelium; Epidemiologic Studies; Event; Exposure to; Functional disorder; Goals; Harvest; Health; Heart; Heart Diseases; Heart failure; Hospitals; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-6; Interleukins; Knockout Mice; Laboratories; Lead; Leukocytes; Link; Literature; Lung; Lung Inflammation; Measurement; Measures; Mediating; Mediator of activation protein; Modeling; Morbidity - disease rate; Mus; Muscle function; Myocardial Infarction; NF-kappa B; Nitric Oxide; Oryctolagus cuniculus; Oxides; Particulate Matter; Pathway interactions; Patients; Phenylephrine; Pollution; Populations at Risk; Process; Production; Proteins; Reactive Oxygen Species; Research; Rho-associated kinase; Risk; Shock; Signal Transduction; Smooth Muscle; Stroke; Therapeutic Intervention; Time; Toxic effect; Transgenic Mice; Ultrafine; Up-Regulation; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; acute coronary syndrome; air filter; ambient particle; constriction; cytokine; heart rhythm; human NOS3 protein; in vivo; insight; insulin signaling; mortality; mouse model; particle; particle exposure; prevent; research study; response; trafficking; urban area; vascular inflammation; vasoconstriction

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。柴油机尾气颗粒物（DEP）是城市交通相关空气污染物的重要组成部分。这 本研究的总体目标是确定 DEP 暴露对血管的影响。我们的广泛 假设空气污染物会影响血管，从而对心血管健康产生不利影响。我们 建议使用年长的 Apo-E 敲除小鼠的成熟 DEP 暴露模型， 自然会发生动脉粥样硬化，这是导致心脏病和中风的潜在疾病。这个型号 代表流行病学研究中显示的面临空气污染不利影响风险的受试者， 即患有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 7 周的小鼠身上采集主动脉，并将这些血管暴露于不同的激动剂中 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，可能参与异常的功能反应 DEP 暴露后的血管。 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，例如一氧化氮 和内皮素，与空气污染暴露后的异常血管反应有关。 4） 定量组织学研究量化 DEP 暴露引起的肺部炎症以及 肺部的颗粒负荷并将其与下游血管的异常血管反应联系起来。 许多流行病学研究表明，接触空气污染颗粒会对人产生不利影响。 心脏和血管。颗粒吸入肺部影响血管的机制， 尚不清楚，也是本提案的重点。这项研究将增进我们对精细沉积如何沉积的见解 肺部的颗粒会对健康产生不利影响，例如引发心绞痛、心脏病发作或中风。 了解这些机制有助于确定潜在的治疗干预措施 防止空气污染物对心脏和血管的不良健康影响。