Ambient Particle Composition and Vascular Dysfunction

环境颗粒成分和血管功能障碍

基本信息

批准号：
8011702
负责人：
Azita K. Madrid-Cuevas
金额：
$ 2.58万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011702
关键词：
Acetylcholine Acetylcysteine Acute Address Adhesions Adverse effects Agonist Air Air Pollution Airborne Particulate Matter Antioxidants Aspirate substance Automobile Driving Biological Biological Availability Blood Circulation Blood Vessels Breathing Calcium Cells Chemicals Cities Cyclooxygenase Inhibitors Data Deposition Diesel Exhaust Discrimination Dose Endothelial Cells Endothelium Enzymes Epithelial Epithelial Cells Excision Exposure to Foundations Functional disorder Gene Expression Generations Geographic Locations Germany Glutathione Goals Health Heart Diseases Human IL8 gene Immune Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-6 Knock-out Knockout Mice Knowledge Laboratories Lead Literature Location Lung Lymphatic Lysosomes Measurement Measures Modeling Mucociliary Clearance Mus Nickel Nitric Oxide Nitric Oxide Synthase Oral Oxidative Stress Particle Size Particulate Matter Pathway interactions Pneumonia Process Production Public Health Reactive Oxygen Species Reporting Research Respiratory System Respiratory tract structure Risk Role Sampling Source TNF gene Testing Tissues Toxic effect Transgenic Model Ultrafine Vascular System Wild Type Mouse Work ambient particle base biological adaptation to stress biological systems cardiovascular disorder risk chemical reaction cytotoxicity extracellular human NOS3 protein in vivo macrophage mouse model neutrophil oil fly ash particle prevent respiratory response ultrafine particle

项目摘要

DESCRIPTION (provided by applicant): Recent studies suggest that particulate matter (PM) derived from different sources with necessarily different physicochemical make up may differ in toxicity. It is important to investigate what components impact human health to assist the regulatory agencies to impose emission standards to reduce the health risk. The goal of this study is to use collected and characterized fine ambient particles, to determine the in vivo systemic vascular dysfunction in a murine model. Particles have been collected over the period of one month from 10 cities within the U.S. and 2 that are in Germany, (Hettstedt and Zerbst). Preliminary data on size and particle composition, as well as cellular response studies that focus on oxidative stress have been completed in our laboratory; these data will be utilized as our foundation for this study. Wild type (WT) and endothelial nitric oxide synthesis knockout (eNOS -/-) mice will be exposed, via trans-oral aspiration, to single or repeated doses of coarse, fine, and ultrafine particles from these locations to determine radical oxidative species formation and subsequent inflammation response and vascular dysfunction. We hypothesize that PM-induced pulmonary inflammation leads to uncoupling of eNOS in the systemic vasculature, which in turn will lead to NOS-generated intracellular radical oxidative stress (ROS). Intracellular oxidative stress induced by PM exposure causes endothelial nitric oxide synthesis inhibition and increases neutrophil adhesion to endothelial cells, causing inflammatory damage. The inflammation-related responses can then be correlated to vascular dysfunction by measuring polymorphonuclear leukocytes (PMN) in the lung in comparison to measurements of PMN in the circulation in WT vs. eNOS -/- mice. The characterization of systemic insult will be assessed by comparing vascular markers of oxidative stress (iNOS, eNOS activities and gene expression, glutathione levels, etc) and dysfunction (contraction response to agonists) in eNOS -/- to WT mice. Usage of the eNOS -/- mice will aid in understanding the mechanisms behind this uncoupling and, to verify this ROS generating pathway.

描述（由申请人提供）：最近的研究表明，来自不同来源、理化成分必然不同的颗粒物（PM）可能具有不同的毒性。重要的是要调查哪些成分会影响人类健康，以协助监管机构实施排放标准以降低健康风险。本研究的目标是使用收集和表征的细小环境颗粒来确定小鼠模型中的体内系统性血管功能障碍。我们在一个月内从美国 10 个城市和德国 2 个城市（赫特施泰特和泽尔布斯特）收集了颗粒物。我们的实验室已完成有关尺寸和颗粒组成的初步数据，以及关注氧化应激的细胞反应研究；这些数据将用作我们这项研究的基础。野生型 (WT) 和内皮一氧化氮合成敲除 (eNOS -/-) 小鼠将通过经口抽吸暴露于来自这些位置的单剂量或重复剂量的粗颗粒、细颗粒和超细颗粒，以确定自由基氧化物质的形成以及随后的炎症反应和血管功能障碍。我们假设 PM 诱导的肺部炎症导致全身血管系统中 eNOS 解偶联，进而导致 NOS 产生细胞内自由基氧化应激 (ROS)。 PM暴露引起的细胞内氧化应激导致内皮一氧化氮合成抑制，并增加中性粒细胞与内皮细胞的粘附，引起炎症损伤。然后，通过测量肺部的多形核白细胞 (PMN) 与 WT 与 eNOS -/- 小鼠循环中的 PMN 测量值进行比较，可以将炎症相关反应与血管功能障碍相关联。通过比较 eNOS -/- 与 WT 小鼠的氧化应激血管标志物（iNOS、eNOS 活性和基因表达、谷胱甘肽水平等）和功能障碍（对激动剂的收缩反应）来评估系统性损伤的特征。使用 eNOS -/- 小鼠将有助于了解这种解偶联背后的机制，并验证这种 ROS 生成途径。