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

描述（由申请人提供）：纳米技术的快速发展将伴随着数百万人接触到含有纳米材料的产品。碳纳米管（CNTs）是设计用于多种用途（电子，工程，医学）的工程纳米材料，但具有与石棉相似的特性，石棉是一种与肺纤维化（组织瘢痕）和间皮瘤（肺胸膜表面的罕见癌症）的发展有关的纤维。我们最近报道，CNTs还会加剧小鼠过敏性哮喘的发展，并增加预先暴露于细菌脂多糖（LPS）的小鼠的肺纤维化。此外，我们发现吸入CNTs的小鼠血小板衍生生长因子（PDGF）和单核细胞趋化蛋白-1 （MCP-1）升高，这是纤维化、哮喘和胸膜疾病的两种重要介质。我们还发现碳纳米管激活肿瘤抑制因子p53，这与间皮瘤有关。本提案的总体目标是利用现有的体外和体内方法来评估不同类型的碳纳米管的暴露和健康影响，这些碳纳米管通过涂覆各种有机或无机剂来修饰其表面化学。本提案中需要验证的具体假设是，吸入碳纳米管通过促进肺和胸膜内的免疫和纤维化反应而造成健康风险；尤其是那些已经患有呼吸道疾病的人。为了验证这一假设，我们将进行以下具体研究：在第1项研究中，我们将利用一种成熟的过敏性哮喘小鼠模型和一种成熟的lps诱导的气道炎症模型，阐明吸入CNTs在体内加剧气道纤维化的机制。在Aim 2中，我们将确定吸入CNTs在肺胸膜表面引起免疫和纤维化反应的机制，以及CNTs诱导的胸膜损伤是否进展为慢性纤维化和/或肿瘤。在Aim 3中，我们将评估CNTs在培养的巨噬细胞、成纤维细胞和间皮细胞中激活的细胞信号通路，这些通路导致促纤维化细胞因子和生长因子的产生，在纤维化、免疫反应和癌症中发挥重要作用。这种创新和新颖的方法将为碳纳米管引起纤维化和胸膜疾病的机制提供有价值的信息，以及患有哮喘等呼吸系统疾病的个体是否有更大的风险。此外，我们将专门修改碳纳米管的表面化学，以确定毒性和疾病易感性是否增加或减少。对碳纳米管促进慢性肺部疾病的分子机制的新见解将提高我们对这些工程纳米材料风险的理解，从而填补一个主要的知识空白。这项工作的广泛影响可以通过为设计更安全的纳米材料提供必要信息，以积极的方式直接影响数百万人的健康和福祉。

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.