Benzene Exposure and Heart Failure

苯暴露和心力衰竭

• 批准号: 10652663
• 负责人: Igor N. Zelko
• 金额: $ 19.56万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 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/10652663
• 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; Cell Separation; Cells; Chemicals; Chemotaxis; Cholesterol; Chronic; Clinical Research; Complex; Data; Development; Dichloromethylene Diphosphonate; Dose; Echocardiography; Endothelial Cells; Endothelium; Endotoxins; Environment; Environmental Pollutants; Epidemiology; Exposure to; Flow Cytometry; Functional disorder; Gene Expression Regulation; Genetic Transcription; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; High Prevalence; Histology; Hospitalization; Human; Hypertrophy; Immune; Immunohistochemistry; Immunologic Stimulation; Infiltration; Inflammation; Inflammatory; Inflammatory Infiltrate; Inhalation; Injury; Insulin Resistance; LCN2 gene; Left; Left ventricular structure; Liposomes; Macrophage; 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; United States; Up-Regulation; Ventricular; Ventricular Remodeling; Xylene; acute coronary syndrome; air filter; cardiovascular health; cardiovascular risk factor; chemokine; cigarette smoke; endothelial stem cell; ethylbenzene; exposed human population; granulocyte; heart function; immune cell infiltrate; improved; inhibitor; insight; 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

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。苯引起的心功能恶化还伴有内皮细胞损伤 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。