Defining the Role of IL-1? in Tungsten-Mediated Cardiovascular Disease

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 NORA cross-sectors
Cardiovascular and Respiratory Health.

Grant Number: 5R21OH012552-02
NIH Institute/Center: ALLCDC
Principal Investigator: Alicia Bolt