PROJECT SUMMARY / ABSTRACT The heavy metals, cadmium, arsenic, and manganese, have been identified at high levels in the air and soil of the Affected Area (proposed Superfund site). Heavy metals released into the environment have a significant effect on respiratory health. Although the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma are complex, the environmental exposure to heavy metals is often overlooked in the development of these diseases. Lower respiratory tract infections (LRTIs) are a main cause of COPD and asthma exacerbations, which contributes to the morbidity and mortality of these diseases. The residents of the Affected Area have 30% higher diagnosed LRTIs than residents from the Control Area. Lung macrophages have a critical role in host defense to respiratory pathogens. Lung macrophages not only initiate an innate immune response to infection and injury, but they are also involved in repair of injury. Alveolar epithelial cells (AEC) are injured during infection that results in lung injury by disruption of the cellular barrier. It is not known if heavy metals regulate the macrophage phenotype to hinder the repair of the AEC barrier function. We hypothesize that exposure to heavy metals exacerbates LRTI and lung injury due to the persistence of a classically activated phenotype in lung macrophages. This persistence impairs the repair of the alveolar epithelium after injury. The goals of Aim 1 are to determine if heavy metal-exposed mice have increased bacterial or viral load, lung injury, and mortality compared to vehicle-exposed mice infected with S. pneumoniae or respiratory syncytial virus (RSV) due to the persistence of classically activated lung macrophages. In Aim 2 we will utilize genetic approaches to determine the mechanism(s) by which macrophages maintain persistent classical activation. The goals of Aim 3 are to determine if macrophage phenotypic switching is impaired in residents from the Affected Area compared to the Control Area and if BAL fluid from residents in the Affected Area impairs wound closure and increases permeability of injured AEC. Studies from Project 3 will define the molecular mechanism(s) by which heavy metal exposure increases LRTIs in residents of the Affected Area and proposed Superfund site, providing a potential therapeutic target to reduce the exacerbations seen in these chronic lung diseases.