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Project 1: Vascular Response to Diesel Exhaust in Humans

项目 1：人体对柴油机尾气的血管反应

基本信息

批准号：
8278529
负责人：
Joel Daniel Kaufman
金额：
$ 32.35万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/8278529
关键词：
Acetylcysteine Acute Air Pollutants Air Pollution Angiotensin II Angiotensin Receptor Animal Model Animals Antioxidants Attenuated Behavior Biological Markers Blood Vessels Breathing Cardiovascular Diseases Cell Culture Techniques Cell model Cells Ceruloplasmin Clinical Code Coronary artery Diesel Exhaust Disease Endothelin-1 Endothelium Epidemiologic Studies Equilibrium Event Exposure to Genes Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Heat shock proteins Hour Human In Vitro Individual Inflammation Mediators Interleukin-6 Kinetics Link Losartan Measurable Measures Mediator of activation protein Modeling Molecular Molecular Profiling Myocardial Infarction Myocardial Ischemia Oxidative Stress Particulate Particulate Matter Pathway interactions Peripheral Blood Mononuclear Cell Physiological Plasma Preproendothelin Prevention Production RNA Receptor, Angiotensin, Type 1 Renin-Angiotensin System Resolution Sampling Scientist Series Smooth Muscle Smooth Muscle Myocytes Supplementation Testing Therapeutic Time Tissue Sample Tissues Toxicogenomics Ultrasonography Urine Variant Work air filter ascorbate base brachial artery constriction cytokine exposed human population free radical oxygen gene therapy genetic variant human subject human tissue in vitro Model insight intervention effect mouse model receptor repository research study response time use trafficking vasoconstriction

项目摘要

Air pollution exposures are associated with ischemic heart diseases including myocardial infarction. Recent observations demonstrate that air pollutants, including fine particulate and diesel exhaust (DE), trigger increased arterial reactivity and vasoconstriction in both human and animal models. We will use inhaled DE to study vascular effects in a clinical setting. The hypothesis is that DE exerts vascular effects via oxidative stress, through one of the well-established mechanisms controlling endothelium and smooth muscle in conductance vessels, altering the balance of constriction and dilation. First, in human subjects, we will test whether the observed vasoconstrictive response in the brachial artery (using ultrasound) following DE exposure is blunted with antioxidant administration, and heightened in individuals with genetic susceptibility to angiotensin II (AT., receptor variant AGTR1 A1166C)). The associated DE-induced changes in soluble mediators such as IL-6, and markers of endothelial activation such as endothelin-1 will be also be determined. Second, we will establish a time course for events occurring with regard to soluble mediators, endothelial activation, and vasoconstriction, using serial studies of each parameter, as well as serial measures of gene transcription in peripheral blood mononuclear cells, and determine if specific effects are blocked by the AT! receptor blocker losartan. We will also determine if DE's vasoconstrictive effects are increased in subjects with a common SNP variant in the gene coding for preproendothelin, a variation which is already associated with hypertensive responses. Third, we will closely integrate our studies with other projects in the DISCOVER Center. We will determine if hypotheses explored in animal and in vitro models can be tested in our human studies. For example, we will determine if DE increases plasma levels of ceruloplasmin and Heat Shock Protein. We will also create a repository of paired human samples exposed to DE and FA, for additional analyses and for incubation with human cells in culture studies. The studies exploit a partnership between clinical and basic scientists to explore the key mechanisms underlying this environmentally-induced disease. We will derive an understanding of the causes of air pollutant-related cardiovascular disease. This information is needed to develop prevention and therapeutic strategies.

空气污染暴露与缺血性心脏病包括心肌梗死有关。最近