Environmental Cadmium and COPD

环境镉与慢性阻塞性肺病

• 批准号: 9789316
• 负责人: Veena B. Antony
• 金额: $ 50.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789316
• 关键词: 3-Dimensional; Address; Affect; Air Pollution; Alabama; Alveolar Cell; Apoptosis; Blood; Blood capillaries; Cadmium; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Cigarette; Clinical; Coal; Code; Collagen; Communities; Complex; Cytoskeletal Proteins; Cytoskeleton; Deposition; Disease; Disease susceptibility; Docking; Dose; Environmental Exposure; Epithelial; Event; Exhalation; Exhibits; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Filament; Generations; Heavy Metals; Homeostasis; Human body; Impairment; Industrialization; Inhalation; Intermediate Filament Proteins; Intermediate Filaments; Laboratories; Life; Lung; Maintenance; Mediating; Membrane; Mesenchymal; Mesenchymal Differentiation; Mitochondria; Modeling; Myofibroblast; N-terminal; Oxidants; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Power Plants; Predisposition; Prevalence; Production; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary function tests; Reporting; Resistance; Resolution; Role; Site; Smoker; Testing; Toxic Environmental Substances; Urine; Vascular Endothelial Cell; Vimentin; Work; X-Ray Computed Tomography; airway hyperresponsiveness; airway obstruction; airway remodeling; cell motility; cigarette smoke; cohort; demographics; early detection biomarkers; human subject; mitochondrial dysfunction; mortality; mouse model; never smoker; novel; novel therapeutics; response; smoking prevalence; superfund site; targeted treatment; therapeutic target; trafficking; 3-Dimensional; Address; Affect; Air Pollution; Alabama; Alveolar Cell; Apoptosis; Blood; Blood capillaries; Cadmium; Cause of Death; Cells; Chronic; Chronic Obstructive Airway Disease; Cigarette; Clinical; Coal; Code; Collagen; Communities; Complex; Cytoskeletal Proteins; Cytoskeleton; Deposition; Disease; Disease susceptibility; Docking; Dose; Environmental Exposure; Epithelial; Event; Exhalation; Exhibits; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Filament; Generations; Heavy Metals; Homeostasis; Human body; Impairment; Industrialization; Inhalation; Intermediate Filament Proteins; Intermediate Filaments; Laboratories; Life; Lung; Maintenance; Mediating; Membrane; Mesenchymal; Mesenchymal Differentiation; Mitochondria; Modeling; Myofibroblast; N-terminal; Oxidants; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphorylation; Plasma; Power Plants; Predisposition; Prevalence; Production; Pulmonary Emphysema; Pulmonary Fibrosis; Pulmonary function tests; Reporting; Resistance; Resolution; Role; Site; Smoker; Testing; Toxic Environmental Substances; Urine; Vascular Endothelial Cell; Vimentin; Work; X-Ray Computed Tomography; airway hyperresponsiveness; airway obstruction; airway remodeling; cell motility; cigarette smoke; cohort; demographics; early detection biomarkers; human subject; mitochondrial dysfunction; mortality; mouse model; never smoker; novel; novel therapeutics; response; smoking prevalence; superfund site; targeted treatment; therapeutic target; trafficking

The lung is a major portal for respirable environmental toxicants including heavy metals such as cadmium (Cd), which is recognized to cause chronic obstructive pulmonary disease (COPD). COPD is the third largest cause of mortality in the US. Airway remodeling with loss of the lumen of small airways and airflow obstruction precede airspace enlargement and emphysema. Airway remodeling is associated with a profusion of airway fibroblasts and an increase in extracellular matrix proteins. Vimentin is an intracellular type 3 filament that can trigger peribronchial fibrosis. The prevalence of COPD is twice as high in a zip code where a Superfund site is located in Birmingham, Alabama when compared to a control zip code with similar demographics and smoking prevalence. We postulate that chronic low dose cadmium (Cd) exposure induces alterations in vimentin-mitochondrial dynamics that results in mitochondrial dysfunction and aberrant activation of peribronchiolar fibroblasts leading to bronchiolar luminal narrowing and subsequent COPD. We will examine this hypothesis in the following specific aims: (1) Determine whether exposure to Cd in a cohort of smokers and never-smokers from a Birmingham community predicts susceptibility to airway remodeling and COPD. (2) Determine the mechanisms by which Cd mediates alterations in vimentin-mitochondrial dynamics to regulate fibroblast activation. (3) Determine whether low dose Cd, or pSer39Vim induced airway remodeling and airspace enlargement in a mouse model of COPD is associated with fibroblast invasion, ECM deposition and apoptosis resistance. These studies will directly address a significant gap in our understanding of how cadmium contributes to the pathogenesis of COPD and the role of vimentin filaments in mitochondrial homeostasis. Early biomarkers of COPD in exhaled breath condensate may help us recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies in patients with COPD.

肺是可呼吸的环境有毒物质的主要门户，包括重金属，例如镉 （CD），被认为会导致慢性阻塞性肺疾病（COPD）。 COPD是第三 美国死亡率最大的原因。气道重塑，损失了小气道和气流的管腔 障碍物先于空域扩大和肺气肿。气道重塑与大量 气道成纤维细胞和细胞外基质蛋白的增加。波形蛋白是一种细胞内3丝 这会触发周围纤维化。在邮政编码中，COPD的患病率是高度的两倍 与具有相似的对照邮政编码相比，超级基金网站位于阿拉巴马州伯明翰 人口统计学和吸烟流行。我们假设慢性低剂量镉（CD）暴露会诱发 波形蛋白线粒体动力学的改变，导致线粒体功能障碍和异常激活 可导致支气管腔狭窄和随后的COPD导致支气管腔的成纤维细胞。我们将检查 以下特定目的中的该假设：（1）确定是否在吸烟者中暴露于CD 伯明翰社区的永不吸烟者预测了气道重塑和COPD的敏感性。 （2） 确定CD介导波形蛋白 - 线粒体动力学改变的机制以调节 成纤维细胞激活。 （3）确定低剂量CD或PSER39VIM是否诱导气道重塑和 COPD小鼠模型中的空域扩大与成纤维细胞侵袭，ECM沉积和 抗凋亡抗性。这些研究将直接解决我们对如何理解的差距 镉有助于COPD的发病机理和波形蛋白丝在线粒体中的作用 稳态。在呼出的呼吸冷凝物中，COPD的早期生物标志物可能有助于我们识别疾病 敏感性。重要的是，这些研究可能为COPD患者提供新的治疗策略。