Benzene Exposure and Heart Failure

苯暴露和心力衰竭

基本信息

批准号：
10528089
负责人：
Igor N. Zelko
金额：
$ 23.48万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10528089
关键词：
Adhesions Affect Air Pollutants Animal Model Animals Anti-Inflammatory Agents Automobile Exhaust Benzene Benzene Exposure Bone Marrow C57BL/6 Mouse CXCL1 gene Cardiac Cardiac Output Cardiotoxicity Cardiovascular Diseases Cells Chemicals Chemotaxis Cholesterol Chronic Clinical Research Complex Data Development Dichloromethylene Diphosphonate Dose Echocardiography Endothelial Cells Endothelium Endotoxins Environmental Pollutants Epidemiology Exposure to Flow Cytometry Gene Expression Genetic Transcription Goals Heart Heart Diseases Heart Hypertrophy Heart failure High Prevalence Histology Hospitalization Human Hypertrophy Immune Immunohistochemistry Infiltration Inflammation Inflammatory Inhalation Injury Insulin Resistance LCN2 gene Left Left ventricular structure Liposomes Mediating MicroRNAs Molecular Morbidity - disease rate Mus Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Neutrophil Infiltration Outcome Pathologic Patients Persons Plasma Process Risk Risk Factors Role S100A8 gene S100A9 gene Signal Transduction Site Source Styrenes TLR4 gene Testing Time Tissues Tobacco smoke Toluene Tumor-infiltrating immune cells United States Up-Regulation Ventricular Ventricular Remodeling Xylene acute coronary syndrome air filter base cardiovascular health cardiovascular risk factor chemokine cigarette smoke endothelial stem cell ethylbenzene exposed human population granulocyte heart function improved inhibitor insight macrophage mimetics monocyte mortality mouse model myocardial injury neutrophil patient prognosis preclinical study pressure recruit sex small molecule small molecule inhibitor toxicant transcriptome sequencing volatile organic compound

项目摘要

Project Summary Long-term exposure air pollutant exposure is recognized as a risk factor for cardiovascular diseases including myocardial ischemia and heart failure. Recent epidemiological and experimental data indicate that many volatile organic compounds including benzene contribute to worsening outcomes in patients with progressive heart disease. Benzene is the most abundant air pollutant mostly generated from automobile exhaust and tobacco smoke. Despite high prevalence of benzene in air-pollutants, little is known about the direct effects of inhaled benzene on heart failure morbidity and mortality in well-controlled animal studies. Our recent studies show that benzene exposure resembling moderate to high levels of human exposure worsens cardiac function in pressure overload-induced mice. The benzene-induced worsening of cardiac functions was accompanied by endothelial activation and infiltration of granulocytes in the heart and upregulation of gene expression for CXCL1 chemokine and alarmin S100A8/A9 complex which promotes neutrophil and monocyte chemotaxis and adhesion through TLR4 and RAGE signaling. Our new preliminary data show that ambient benzene exposure causes endothelial activation/injury in humans and chronic low dose exposure stimulates endothelial activation/injury in mice. Using animal model of pressure overload-induced cardiac dysfunction, we will examine the effects of environmental benzene exposure on cardiac dysfunction (echocardiography, cardiac hypertrophy, analysis of composition and activation status of infiltrating immune cells) during heart remodeling (Aim 1), and examine the molecular mechanisms by which benzene exacerbate cardiac dysfunction (Aim 2). Successful completion of these studies will, for the first time, show how benzene affect cardiac function in patients with progressing heart failure and provide mechanistic insight into this process.

项目概要长期接触空气污染物被认为是心血管疾病的危险因素，包括心肌缺血和心力衰竭。最近的流行病学和实验数据表明，许多不稳定的包括苯在内的有机化合物会导致进展性心脏病患者的预后恶化疾病。苯是最丰富的空气污染物，主要由汽车尾气和烟草产生抽烟。尽管空气污染物中苯的含量很高，但人们对吸入苯的直接影响知之甚少。在严格对照的动物研究中，苯对心力衰竭发病率和死亡率的影响。我们最近的研究表明苯暴露与中度至高水平的人体暴露类似，会导致压力下的心脏功能恶化超负荷诱导的小鼠。苯引起的心脏功能恶化伴随着内皮细胞心脏中粒细胞的激活和浸润以及 CXCL1 趋化因子基因表达的上调和警报素 S100A8/A9 复合物，通过促进中性粒细胞和单核细胞趋化性和粘附 TLR4 和 RAGE 信号传导。我们的新初步数据表明，环境中的苯暴露会导致内皮细胞损伤人类的激活/损伤和慢性低剂量暴露会刺激小鼠的内皮激活/损伤。使用压力超负荷引起的心脏功能障碍的动物模型，我们将检查环境的影响苯暴露对心脏功能障碍的影响（超声心动图、心脏肥大、成分分析和心脏重塑（目标 1）期间浸润免疫细胞的激活状态，并检查分子苯加剧心脏功能障碍的机制（目标 2）。成功完成这些研究将首次展示苯如何影响进展性心力衰竭患者的心功能提供对此过程的机械洞察。