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

描述(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(CNT)是一种设计用于多种用途(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(组织疤痕形成)和间皮瘤(一种罕见的肺部胸膜表面癌症)的发展有关的纤维。我们最近报道，碳纳米管还加剧了小鼠过敏性哮喘的发展，并增加了预先暴露于细菌脂多糖(LPS)的小鼠的肺纤维化。此外，我们发现吸入碳纳米管的小鼠增加了血小板衍生生长因子(PDGF)和单核细胞趋化蛋白-1(MCP-1)，这是纤维化、哮喘和胸膜疾病的两个重要介质。我们还发现，碳纳米管激活了与间皮瘤有关的肿瘤抑制基因P53。这项建议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试剂来修饰其表面化学。这项建议中要检验的具体假设是，吸入碳纳米管会促进肺和胸膜内的免疫反应和纤维化反应，从而对健康构成风险；特别是在既往患有呼吸道疾病的人中。在目标1中，我们将利用已建立的过敏性哮喘小鼠模型和脂多糖诱导的呼吸道炎症模型，在体内阐明吸入碳纳米管加重呼吸道纤维化的机制。在目标2中，我们将确定吸入碳纳米管引起肺胸膜表面免疫和纤维化反应的机制，以及碳纳米管诱导的胸膜损伤是否进展为慢性纤维化和/或肿瘤。在目标3中，我们将评估碳纳米管在培养的巨噬细胞、成纤维细胞和间皮细胞中激活的细胞信号通路，这些信号通路导致促纤维化细胞因子和生长因子的产生，这些细胞因子和生长因子在纤维化、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提供有价值的信息，了解碳纳米管导致纤维化和胸膜疾病的机制，以及患有哮喘等先前存在的呼吸系统疾病的个人是否面临更大的风险。此外，我们将专门对碳纳米管的表面化学进行修饰，以确定毒性和疾病易感性是增加还是降低。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的风险的理解，从而填补一个重大的知识空白。这项工作的广泛影响可以为设计更安全的纳米材料提供必要的信息，从而以积极的方式直接影响数百万人的健康和福祉。 与公共卫生相关：到2015年，全世界用于技术研发的资金预计将超过1万亿美元。碳纳米管被认为是纳米技术中最有前途的材料之一，在医学、工业和消费品方面有着广泛的应用。对于其中的许多应用，纳米管将被各种有机或无机试剂包覆，以改变其表面化学。碳纳米管的健康风险尚不清楚。然而，它们的针状结构让人想起几十年前因其优越的绝缘特性而被开发的石棉纤维，但它导致了胸膜肺癌(间皮瘤)和肺纤维化的全球大流行。由于电子和结构工程中各种用途的产量增加，人类和环境对碳纳米管的暴露不可避免地增加。我们最新公布的数据显示，吸入纳米管显著增加了与过敏性哮喘相关的呼吸道纤维化。此外，我们最近未发表的研究结果表明，吸入纳米管会引起小鼠肺内胸膜间皮细胞表面的免疫和纤维化反应。这一令人震惊的观察结果增加了碳纳米管可能对人类健康和环境构成严重威胁的可能性。

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.