Project Summary/Abstract Inhalation of particulate matter is a known risk factor for the development of cardiovascular disease. Tungsten is an emerging environmental contaminant, particularly in occupational settings such as heavy metal manufacturing and military, where ambient air concentrations have been reported as high as 3.1 mg/m3 and exposure is associated with increased risk of pulmonary diseases. However, limited studies have investigated the systemic consequences of this pulmonary damage. Recent epidemiological data have established that increased exposure to tungsten leads to increased risk of cardiovascular diseases and stroke. However, no studies have taken a systematic mechanistic approach to investigate how exposure to tungsten affects the heart or cardiovascular disease risk factors. The long-term goal in our program is to define the long-term health consequences of chronic exposure to tungsten and determine the underlying molecular mechanisms of toxicity. We have strong preliminary data in mice, indicating that a single 4-hour inhalation exposure to tungsten particulates results in persistent deposition of tungsten in the lungs, acute pulmonary inflammation characterized by elevated levels of IL-1β, and early signs of fibrosis. Subsequently, four, 4-hour exposures to tungsten over the course of 2 weeks result in increased expression of IL-1β and other pro-inflammatory and pro-fibrogenic markers in the heart and early signs of cardiac dysfunction. Our central hypothesis is that tungsten exposure drives cardiovascular disease development through activation of IL-1β signaling and enhanced cardiac remodeling leading to fibrosis. In Aim 1, we will use an innovative experimental design to determine how chronic inhalation exposure to tungsten affects cardiac function and the development of cardiovascular disease, alone or through further exacerbation of angiotensin II-mediated cardiovascular disease (two-hit model). We will also define the role of inflammation and cardiac remodeling in disease pathogenesis, define systemic mediators of disease following this pulmonary insult, and distinguish tungsten- specific particulate effects through comparison with an active control particle. In Aim 2, we will use an IL-1β specific monoclonal antibody to block IL-1β signaling to investigate the impact of IL-1β signaling on tungsten- mediated inflammation and remodeling processes in disease development. This work is innovative and significant because it utilizes state-of-the art tools to investigate molecular mechanisms driving tungsten- mediated cardiovascular disease. Discoveries from these studies will impact Research to Practice initiatives to inform identification of at-risk occupational populations, development of monitoring programs, and identification of effective countermeasures to block immune fibroblast crosstalk, which could mitigate cardiovascular disease risk. This proposal directly addresses NIOSH Strategic Plan Research Goal #1 and NO...