Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis

碳纳米管诱导纤维化的预测及机制

• 批准号: 8268403
• 负责人: Yon Rojanasakul
• 金额: $ 36.63万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8268403
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Affect; Alveolar; Alveolar wall; Angiogenic Factor; Animals; Biological; Biological Assay; Biological Markers; Biological Models; Caliber; Carbon Nanotubes; Cell Proliferation; Cells; Characteristics; Chemicals; Chemistry; Collagen; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Delivery Systems; Early Diagnosis; Early treatment; Environmental and Occupational Exposure; Epithelial; Evaluation; Exposure to; Extracellular Matrix; Fibroblasts; Fibrosis; Foundations; Generations; Goals; Growth Factor; Health; Human; In Vitro; Industrial Product; Industry; Inflammation; Investigation; Knowledge; Lung; Lung Inflammation; Lung diseases; Mediating; Mediator of activation protein; Molecular Target; Mus; Nanotechnology; Outcome; Oxidation-Reduction; Pathogenesis; Play; Process; Production; Property; Public Health; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Research Design; Risk; Risk Assessment; Role; Science; Screening procedure; Signal Pathway; Signal Transduction; Solutions; Source; Structure of parenchyma of lung; System; Testing; Therapeutic; Toxic effect; Transforming Growth Factors; United States; United States National Institutes of Health; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; angiogenesis; base; cellular targeting; cytokine; fibrogenesis; in vitro Model; in vivo; interstitial; mouse model; nanomaterials; nanoparticle; public health relevance; response; single walled carbon nanotube; trend

DESCRIPTION (provided by applicant): Project Summary: Environmental and occupational exposures to manufactured nanomaterials have markedly increased during the past recent years, and in all likelihood this trend will continue as new nanomaterials are being increasingly produced and used by various industries. This trend has been of great concern as the adverse health effects of nanomaterials are relatively unknown and understudied. Recent studies have shown that pulmonary exposure to carbon nanotubes (CNT), one of the most widely used nanomaterials in industry, results in rapid and progressive interstitial lung fibrosis in animals without causing persistent lung inflammation, which is normally associated with other known fibrogenic agents. This unusual fibrogenic effect of CNT raises important health issues since the exposure could result in deadly and incurable lung fibrosis. We hypothesize that CNT, due to their unique properties such as exceptionally small size, large aspect ratio, and chemical composition can rapidly enter the lung, penetrate the alveolar epithelial barrier, and interact with specific lung cells such as interstitial lung fibroblasts to induce fibroproliferation and extracellular matrix accumulation, which are characteristics of lung fibrosis. We also propose that such induction is mediated by signaling cascades that involve phosphatidylinositol-3-kinase(PI3K)/Akt activation and redox regulation of the profibrogenic and angiogenic factors such as TGF-b and VEGF. In Aim 1, we will determine the impact of certain nanoparticle characteristics (e.g., diameter, aspect ratio, dispersion status, and chemistry) on CNT-induced lung fibrosis and develop rapid in vitro screening assays which may be predictive of the in vivo fibrogenic response. Aim 2 will delineate key signaling pathways and fibrogenic factors involved in the induction of fibrosis by CNT in order to identify potential biomarkers and drug targets for diagnosis and treatment of the disease. Aim 3 will investigate the involvement of angiogenesis and angiogenic factors in the development of pulmonary fibrosis induced by CNT. Aim 4 will determine redox regulation of CNT-induced fibrogenesis and angiogenesis and elucidate the underlying mechanisms. Through this application, we expect to define key nanoparticle characteristics and a set of in vitro screening assays for evaluation of the potential fibrogenicity of nanoparticles in vivo. Such information will be important for safe use of nanotechnology. The proposed studies will also identify molecular targets for early detection and treatment of fibrotic lung diseases caused by nanomaterials. PUBLIC HEALTH RELEVANCE: Relevance to Public Health: Nanotechnology presents enormous opportunities to create new and better products for industrial applications and for diagnosis and treatment of diseases. However, the potential adverse health effects of nanomaterials are unclear since information is lacking that would allow prediction of the biological activity of these new materials. This project will address NIH goals and public health needs by 1) determining key physiochemical properties of nanomaterials that contribute to their pulmonary toxicity and fibrogenicity, 2) developing rapid screening assays for prediction of the fibrogenic effects of nanomaterials, and 3) elucidating the underlying mechanisms of pulmonary fibrosis induced by nanomaterials in order to identify specific biomarkers and drug targets for early diagnosis and treatment of the disease.

描述（由申请人提供）： 项目摘要：在过去的几年中，人造纳米材料的环境和职业暴露显着增加，并且随着各行业越来越多地生产和使用新的纳米材料，这种趋势很可能将持续下去。由于纳米材料对健康的不利影响相对未知且研究不足，因此这一趋势备受关注。最近的研究表明，肺部接触碳纳米管（CNT）是工业中使用最广泛的纳米材料之一，会导致动物快速、进行性间质性肺纤维化，但不会引起持续性肺部炎症，而这种炎症通常与其他已知的纤维形成剂有关。碳纳米管的这种不寻常的纤维化作用引发了重要的健康问题，因为接触碳纳米管可能导致致命且无法治愈的肺纤维化。我们假设碳纳米管由于其尺寸极小、长宽比大和化学成分等独特的性质，可以快速进入肺部，穿透肺泡上皮屏障，并与特定的肺细胞（如间质性肺成纤维细胞）相互作用，诱导纤维增殖和细胞外基质堆积，这是肺纤维化的特征。我们还提出，这种诱导是通过信号级联介导的，涉及磷脂酰肌醇-3-激酶 (PI3K)/Akt 激活以及促纤维生成和血管生成因子（如 TGF-b 和 VEGF）的氧化还原调节。在目标 1 中，我们将确定某些纳米颗粒特性（例如直径、长宽比、分散状态和化学性质）对 CNT 诱导的肺纤维化的影响，并开发可预测体内纤维化反应的快速体外筛选测定法。目标 2 将描述 CNT 诱导纤维化所涉及的关键信号通路和纤维形成因子，以确定诊断和治疗该疾病的潜在生物标志物和药物靶点。目标 3 将研究血管生成和血管生成因子在 CNT 诱导的肺纤维化发展中的作用。目标 4 将确定 CNT 诱导的纤维生成和血管生成的氧化还原调节，并阐明其潜在机制。通过该应用，我们期望定义关键的纳米颗粒特征和一组体外筛选测定，以评估纳米颗粒在体内的潜在纤维形成性。这些信息对于纳米技术的安全使用非常重要。拟议的研究还将确定用于早期检测和治疗由纳米材料引起的纤维化肺病的分子靶标。 公共卫生相关性： 与公共卫生的相关性：纳米技术为工业应用以及疾病诊断和治疗创造新的、更好的产品提供了巨大的机会。然而，纳米材料对健康的潜在不利影响尚不清楚，因为缺乏可以预测这些新材料的生物活性的信息。该项目将通过以下方式满足 NIH 目标和公共卫生需求：1) 确定纳米材料的关键理化特性，这些特性有助于其肺毒性和纤维形成性；2) 开发快速筛选方法来预测纳米材料的纤维形成效应；3) 阐明潜在机制纳米材料诱导的肺纤维化的研究，以确定特定的生物标志物和药物靶点，用于疾病的早期诊断和治疗。