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毒物，在全世界的水中含量很高。超过1.5亿 人们居住的地区砷含量明显高于 WHO 和 USEPA 推荐的指南（10 ppb)。肺是砷中毒的靶器官。智利、孟加拉国、内蒙古和印度的人体研究报告 印度西孟加拉邦地区的研究表明，通过饮用水长期接触砷与砷的增加有关。 慢性咳嗽、慢性支气管炎、气短、肺功能下降以及阻塞性或限制性的发生率 肺部疾病。我们实验室和其他实验室的证据引起了人们越来越多的关注，即即使砷浓度为 10 ppb， 可以改变肺的结构和功能。此外，还有越来越多的证据表明，在子宫内和产后早期暴露 砷会导致肺结构和功能的改变，从而导致慢性肺病的发展 在以后的生活中。在美国的农村地区，例如西南部地区，很大一部分人口 从私人、不受监管的水井获取水，这些水井中砷的浓度可能远远超过 10 ppb 的水平。在 此外，干旱的美国西南部的灰尘中可能含有高浓度的砷和其他污染物。吸入 这些粉尘会增加肺部对砷的接触，从而模拟砷摄入引起的肺部疾病。数据很少 关于接触含砷粉尘的风险以及摄入砷之间的潜在相互作用 水和灰尘暴露。尽管人们公认肺是砷中毒的主要靶器官，但有关研究 生命早期砷暴露后非恶性肺病的生物标志物或机制有限。一 例外的是 Club（以前称为 Clara）细胞分泌蛋白（以下简称 CC16），它在血液和肺部中显着减少 目前吸烟者，与随后气流受限的发生率降低、肺功能加速衰退有关 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以及对肺功能恶化的直接作用 CC16 预防慢性肺部疾病。然而，CC16 在砷引起的肺异常中的特定功能 仍然不明确。我们的总体目标是确定砷改变 CC16 生产的机制以及 早年接触砷后，CC16 减少在改变肺结构和功能中的作用。两个目标将是 已解决。目标 1 将确定 CC16 在砷诱导的肺结构和功能改变中的作用 生命早期暴露和 Aim2 将确定砷暴露对 CC16 产生的影响及其在 肺。我们的研究结果将确定 CC16 作为生命早期砷暴露和未来砷暴露生物标志物的有效性。 评估砷对长期肺部健康的毒性。阐明的机制也将有助于建立治疗方法 治疗砷引起的肺部疾病的干预措施。