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

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.

肺是呼吸性环境毒物的主要入口，包括镉等重金属。 (Cd)，它被认为会导致慢性阻塞性肺疾病(COPD)。慢性阻塞性肺病是第三种 是美国最大的死亡原因。小气道管腔和气流丧失时的气道重塑 梗阻先于空域扩大和肺气肿。气道重塑与过度充盈有关 呼吸道成纤维细胞的数量和细胞外基质蛋白的增加。波形蛋白是一种细胞内的3型细丝 这可能会引发支气管周围纤维化。慢性阻塞性肺病的患病率在邮政编码是两倍 超级基金网站位于阿拉巴马州伯明翰，与类似的控制邮政编码相比 人口统计学和吸烟率。我们推测慢性低剂量镉暴露可诱导 导致线粒体功能障碍和异常激活的波形蛋白-线粒体动力学改变 细支气管周围成纤维细胞导致细支气管腔狭窄和随后的慢性阻塞性肺疾病。我们将研究 这一假设的具体目的如下：(1)确定吸烟者队列中是否暴露于Cd 来自伯明翰社区的不吸烟者预测易患呼吸道重塑和慢性阻塞性肺病。(2) 确定镉介导波形蛋白-线粒体动力学改变以调节的机制 成纤维细胞激活。(3)确定小剂量Cd或pSer39Vim是否诱导气道重塑和 COPD小鼠模型中空隙扩大与成纤维细胞侵袭、细胞外基质沉积和 抗细胞凋亡。这些研究将直接解决我们在理解如何 镉在COPD发病机制中的作用及线粒体波形蛋白细丝的作用 动态平衡。呼气冷凝液中COPD的早期生物标志物可能有助于我们识别疾病 敏感度。重要的是，这些研究可能为COPD患者提供新的治疗策略。