Arsenic exposure, CC16 and its effect on pulmonary function

砷暴露、CC16及其对肺功能的影响

• 批准号: 9308642
• 负责人: Yin Chen
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308642
• 关键词: Address; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Area; Arsenic; Bangladesh; Biological; Biological Markers; Blood; Breathing; Chile; Chronic; Chronic Bronchitis; Chronic lung disease; Clara cell-specific protein; Coughing; Data; Deterioration; Development; Dust; Epidemiology; Epithelial Cells; Etiology; Exposure to; Gene Expression; Guidelines; Health; Human; Impairment; In Vitro; Incidence; India; Inflammation; Ingestion; Inner Mongolia; Knockout Mice; Laboratories; Lead; Life; Lung; Lung diseases; Modeling; Molecular; Mus; Non-Malignant; Organ; Pathway interactions; Population; Privatization; Production; Proteins; Publications; Reporting; Repression; Respiratory physiology; Risk; Role; Route; Secretory Cell; Serum; Set protein; Shortness of Breath; Side; Signal Pathway; Smoker; Smoking; Southwestern United States; Stream; Structure; Testing; Therapeutic Intervention; Toxic Environmental Substances; Toxic effect; Tretinoin; United States; Water; Withdrawal; airway inflammation; cigarette smoking; cohort; drinking water; early life exposure; environmental tobacco smoke exposure; follow-up; functional restoration; in utero; in vivo; lung development; mortality; mouse model; novel; overexpression; postnatal; pulmonary function; response; rural area

Abstract Arsenic is a ubiquitous environmental toxicant, found in high concentrations in water worldwide; more than 150 million people live in areas with the arsenic content significantly higher than the WHO and USEPA recommended guidelines (10 ppb).The lung is a target organ for arsenic toxicity. Reports from human studies in Chile, Bangladesh, Inner Mongolia and the West Bengal region of India show that chronic exposure to arsenic via drinking water is correlated with increased incidence of chronic cough, chronic bronchitis, shortness of breath, decreased lung function, and obstructive or restrictive lung disease. Evidence from our laboratory and others have contributed to a growing concern that even at 10 ppb, arsenic can alter lung structure and function. In addition, there is also growing evidence that in utero and early postnatal exposures to arsenic can lead to alterations in lung structure and function that contribute to the development of chronic lung disease later in life. In rural areas of United States such as in the southwestern region, a significant percentage of the population receives their water from private, unregulated wells where concentrations of arsenic can far exceed the 10 ppb level. In addition, dusts in the arid Southwestern United States can contain high levels of arsenic and other contaminants. Inhalation of these dusts can increase lung exposures to arsenic that mimic arsenic ingestion induced lung disease. Little data exist concerning the risk from exposure to arsenic containing dusts and the potential interactions between arsenic ingestion in water and dust exposures. Despite the accepted fact that the lung is a major target organ for arsenic toxicity, studies on biomarkers or mechanisms of non-malignant lung diseases following early life arsenic exposures are limited. One exception is Club (formerly Clara) cell secretory protein (hereafter CC16) that is dramatically reduced in blood and lungs of current smokers and is associated with decreased subsequent incidence of airflow limitation, accelerated decline of lung function, and mortality. Studies strongly support CC16 as a biomarker for lung function deterioration and a direct role for CC16 in protecting against chronic lung disease. However, specific function for CC16 in arsenic-induced lung abnormality remains ill-defined. Our overall objective is to determine the mechanism by which arsenic alters CC16 production and the role of reduced CC16 in altering lung structure and function following early life exposure to arsenic. Two Aims will be addressed. Aim.1 will determine the role of CC16 in arsenic-induced lung structural and functional alterations following early life exposures and Aim2 will determine the effect of arsenic exposure on CC16 production and its mode of action in the lung. Results from our study will establish the validity of CC16 as a biomarker for early life arsenic exposure and for the assessment of arsenic toxicity on long-term lung health. The elucidated mechanism will also help to establish therapeutic interventions in the treatment of arsenic-induced lung disease.

抽象的 砷是一种普遍存在的环境有毒物质，在全球水中较高浓度。超过1.5亿 人们居住在砷含量的地区明显高于WHO和USEPA建议的准则（10个 ppb）。肺是砷毒性的靶心器官。来自智利，孟加拉国，内蒙古和人类研究的报告 印度西孟加拉邦地区表明，长期通过饮用水暴露于砷与增加有关 慢性咳嗽，慢性支气管炎，呼吸急促，肺功能降低以及阻塞性或限制性的发生率 肺部病。我们实验室和其他人的证据促成了人们日益关注的问题，即使在10 ppb，砷 可以改变肺结构和功能。此外，还有越来越多的证据表明，在子宫和早期出生后暴露 砷可以导致肺结构和功能改变，这有助于慢性肺部疾病的发展 后来生活。在美国的农村地区，例如西南地区 从私人，不受管制的井中接收水，砷的浓度远远超过了10 ppb的水平。在 此外，美国西南部干旱的尘埃可能含有高水平的砷和其他污染物。吸入 这些尘埃可以增加对模仿砷摄入诱导肺部疾病的砷的肺暴露。很少有数据 关于从含有灰尘的砷的风险以及砷摄入之间的潜在相互作用的风险 水和灰尘暴露。尽管公认的事实是肺是砷毒性的主要目标器官，但研究 早期砷暴露后的非恶性肺疾病的生物标志物或机制受到限制。一 例外是俱乐部（以前是克拉拉）细胞分泌蛋白（以下简称CC16），该蛋白在血液和肺中大大减少 目前的吸烟者，与随后的气流限制发生率降低有关，肺的下降加速下降 功能和死亡率。研究强烈支持CC16作为肺功能恶化的生物标志物，而直接作用 CC16预防慢性肺部疾病。但是，砷诱导的肺异常中CC16的特定功能 仍然不确定。我们的总体目标是确定砷改变CC16的产生和 降低CC16在早期寿命暴露后改变肺结构和功能中的作用。两个目标是 解决。 AIM.1将确定CC16在砷诱导的肺结构和功能改变之后的作用 早期生活暴露和AIM2将确定砷暴露对CC16生产及其行动方式的影响 肺。我们研究的结果将确定CC16作为早期砷暴露的生物标志物的有效性 评估砷对长期肺健康的毒性。阐明的机制也将有助于建立治疗性 治疗砷诱导的肺部疾病的干预措施。