Arsenic exposure, CC16 and its effect on pulmonary function

摘要 砷是一种普遍存在的环境毒物，在世界各地的水中发现高浓度；超过1.5亿 人们生活在砷含量显著高于世卫组织和美国环保局建议指南的地区(10 肺是砷中毒的靶器官。来自智利、孟加拉国、内蒙古和中国的人体研究报告 印度西孟加拉邦地区表明，通过饮用水长期接触砷与增加 慢性咳嗽、慢性支气管炎、呼吸急促、肺功能减退、梗阻或限制性 肺部疾病。来自我们实验室和其他实验室的证据加剧了人们的担忧，即使在10ppb的情况下，砷 可以改变肺的结构和功能。此外，也有越来越多的证据表明，在子宫和出生后早期暴露于 砷可导致肺结构和功能的改变，从而导致慢性肺部疾病的发生。 在以后的生活中。在美国的农村地区，如西南部地区，相当大比例的人口 他们的水来自私人的、不受监管的水井，那里的砷浓度可能远远超过10ppb。在……里面 此外，美国西南部干旱地区的粉尘可能含有高水平的砷和其他污染物。吸入 其中，粉尘会增加肺部对砷的暴露，类似于砷摄取引起的肺部疾病。几乎没有数据存在 关于接触含砷粉尘的风险和砷摄入量之间的潜在相互作用 接触到水和灰尘。尽管公认的事实是肺是砷中毒的主要靶器官，但对 早期接触砷引起的非恶性肺部疾病的生物标志物或机制有限。一 例外的是Club(前身为Clara)细胞分泌蛋白(以下简称CC16)，它在血液和肺组织中显著减少 目前的吸烟者，并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。研究有力地支持CC16作为肺功能恶化的生物标志物，并在 CC16在预防慢性肺部疾病中的作用。然而，CC16在砷致肺异常中的特殊功能 仍然没有明确的定义。我们的总体目标是确定砷改变CC16生产和 降低的CC16在早期砷暴露后肺结构和功能改变中的作用。两个目标将是 地址。Aim.1将确定CC16在以下砷诱导的肺结构和功能改变中的作用 早期生命暴露和AIM2将决定砷暴露对CC16产生的影响及其在 肺部。我们的研究结果将确定CC16作为早期生命砷暴露的生物标志物的有效性，以及 砷毒性对长期肺部健康的评估。阐明的机制也将有助于建立治疗 砷所致肺部疾病的治疗干预。

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.