Arsenic exposure, CC16 and its effect on pulmonary function

摘要 砷是一种普遍存在的环境毒物，在全球范围内的水中发现高浓度;超过1.5亿 人们生活在砷含量明显高于世界卫生组织和美国环保局推荐的指导方针的地区（10 肺是砷中毒的靶器官。来自智利、孟加拉国、内蒙古和 印度西孟加拉地区表明，通过饮用水长期接触砷与 慢性咳嗽、慢性支气管炎、呼吸短促、肺功能下降和阻塞性或限制性 肺病。来自我们实验室和其他实验室的证据使人们越来越担心，即使在10 ppb， 会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的接触 砷会导致肺结构和功能的改变，从而导致慢性肺部疾病的发展。 在以后的生活中在美国的农村地区，如西南地区， 他们从私人的、不受管制的威尔斯井中取水，这些井中的砷浓度可能远远超过10 ppb的水平。在 此外，美国西南部干旱地区的灰尘可能含有高水平的砷和其他污染物。吸入 这些粉尘中的一部分可以增加肺对砷的暴露，这类似于砷摄入引起的肺部疾病。数据很少 关于暴露于含砷粉尘的风险以及摄入砷与 水和灰尘暴露。尽管肺是砷中毒的主要靶器官这一公认事实， 生命早期砷暴露后的非恶性肺病的生物标志物或机制是有限的。一 例外的是Club（以前称为Clara）细胞分泌蛋白（下文称为CC 16），其在患有哮喘的人的血液和肺中显著减少。 目前吸烟者，并与随后气流限制的发生率降低，肺功能加速下降有关。 功能和死亡率。研究强烈支持CC 16作为肺功能恶化的生物标志物， CC 16预防慢性肺部疾病然而，CC 16在砷诱导的肺异常中的特异性功能 仍然不明确。我们的总体目标是确定砷改变CC 16产量的机制， 减少CC 16在改变早期生活暴露于砷后的肺结构和功能中的作用。两个目标将是 处理。目的1将确定CC 16在砷诱导的肺结构和功能改变中的作用， 早期生活暴露和Aim 2将决定砷暴露对CC 16产生的影响及其在 肺我们的研究结果将确立CC 16作为早期生活砷暴露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方法 治疗砷引起的肺病的干预措施。

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.