Lung Toxicity of Carbon Nanotubes in Models of Pre-Existing Respiratory Disease

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DESCRIPTION (provided by applicant): Rapid advances in nanotechnology will be accompanied by the exposure of millions of individuals to products containing nanomaterials. Carbon Nanotubes (CNTs) are engineered nanomaterials designed for multiple uses (electronics, engineering, medicine), but have properties similar to asbestos, a fiber that is linked with the development of pulmonary fibrosis (tissue scarring) and mesothelioma (a rare cancer on the pleural surface of the lung). We recently reported that CNTs also exacerbate the development of allergic asthma in mice and increase pulmonary fibrosis in mice pre-exposed to bacterial lipopolysaccharide (LPS). Moreover, we found that mice which inhaled CNTs have increased platelet-derived growth factor (PDGF) and monocyte chemotactic protein-1 (MCP-1), two important mediators of fibrosis, asthma, and pleural disease. We also found that CNTs activate the tumor suppressor p53, which is implicated in mesothelioma. The overall goal of this proposal is to leverage existing in vitro and in vivo approaches to assess exposure and health effects of different types of carbon nanotubes that have modification of their surface chemistry through coating with various organic or inorganic agents. The specific hypothesis to be tested in this proposal is that inhaled CNTs pose a health risk by promoting immune and fibrotic reactions within the lung and pleura; particularly in individuals with pre-existing respiratory disease. The following specific aims will be carried out to test this hypothesis: In Aim 1, we will elucidate mechanisms through which inhaled CNTs exacerbate airway fibrosis in vivo using a well-established mouse model of allergic asthma and a well-established model of LPS-induced airway inflammation. In Aim 2, we will determine mechanisms through which inhaled CNTs cause immune and fibrotic reactions at the pleural surface of the lung, and whether CNT-induced pleural injury progresses to chronic fibrosis and/or neoplasia. In Aim 3, we will evaluate cell signaling pathways activated by CNTs in cultured macrophages, fibroblasts, and mesothelial cells that lead to the production of pro-fibrogenic cytokines and growth factors that play important roles in fibrosis, immune reactions, and cancer. This innovative and novel approach will provide valuable information on mechanisms through which carbon nanotubes cause fibrosis and pleural disease, and whether individuals with pre- existing respiratory disease such as asthma are at greater risk. Moreover, we will specifically modify the surface chemistry of carbon nanotubes to determine whether toxicity and disease susceptibility is increased or decreased. The new insights into the molecular mechanisms through which carbon nanotubes promote chronic lung disease will improve our understanding of the risk of these engineered nanomaterials and thereby fill a major knowledge gap. The broad impact of this work could directly affect the health and well-being of millions of people in a positive way by providing essential information for the design of safer nanomaterials. PUBLIC HEALTH RELEVANCE: The worldwide funding devoted to anotechnology research and development is expected to exceed $1 trillion by 2015. Carbon nanotubes are considered one of the most promising materials in nanotechnology and have numerous applications in medicine, industry and consumer products. For many of these applications, nanotubes will be coated with various organic or inorganic agents to modify their surface chemistry. The health risk of carbon nanotubes is unknown. However, their needle-like structure is reminiscent of asbestos fibers, which were exploited decades ago because of their superior insulating characteristics, but caused a worldwide pandemic of pleural lung cancer (mesothelioma) and pulmonary fibrosis. Human and environmental exposure to carbon nanotubes is inevitably increasing due to increased production for a variety of uses in electronics and structural engineering. Our most recent published data show that inhaled nanotubes significantly increase airway fibrosis associated with allergic asthma. Moreover, our recent unpublished findings show that inhaled nanotubes cause immune and fibrotic reactions on the pleural mesothelial surface in the lungs of mice. This alarming observation raises the possibility that carbon nanotubes could pose a serious threat to human health and the environment.