Project 3: Diesel Exhaust, Vascular Response & Systemic Inflammation

与交通相关的空气污染与心脏病的恶化有关，具体地说，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入院治疗 疾病。柴油车尾气颗粒物(DEP)是城市交通相关大气污染物的重要组成部分。这个 这项研究的总体目标是确定DEP暴露对血管的影响。我们的大妈 假设空气污染物会影响血管，从而对心血管健康造成不利影响。我们 建议使用已建立的老年Apo-E基因敲除小鼠暴露于DEP的模型， 自然地发生动脉粥样硬化，这是导致心脏病发作和中风的潜在疾病。这款车 代表流行病学研究显示的空气污染不良影响的风险受试者， 即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周的小鼠采集主动脉，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)确定不同的路径 在血管内皮细胞中被激活，可能参与了异常的功能反应 暴露于DEP后的血管。3)检测循环中的促炎介质 包括急性期蛋白、细胞因子和白细胞以及一氧化氮等血管活性介质 以及与暴露在空气污染后的异常血管反应有关的内皮素。4) 定量组织学研究，以量化DEP暴露所致的肺部炎症以及 肺中的颗粒负荷，与下游血管的异常血管反应有关。 许多流行病学研究表明，接触空气污染颗粒物会对人体产生不良影响 心脏和血管。吸入颗粒物到肺中影响血管的机制， 是不清楚的，也是这项提案的重点。这项研究将推进我们对罚款如何沉积的洞察 肺中的颗粒物会对健康造成不良影响，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哪些潜在的治疗干预可以 预防空气污染物对心脏和血管的不良健康影响。

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.