Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis

描述(由申请人提供)： 项目摘要：在过去的几年里，环境和职业对人造纳米材料的暴露显著增加，而且随着新的纳米材料越来越多地被各个行业生产和使用，这一趋势很可能会继续下去。这一趋势引起了人们的极大关注，因为纳米材料对健康的不利影响相对未知和研究不足。最近的研究表明，肺暴露于碳纳米管(CNT)是工业上应用最广泛的纳米材料之一，可导致动物快速和进行性的间质性肺纤维化，而不会引起持续性的肺部炎症，而这通常与其他已知的致纤维化因素有关。碳纳米管的这种不同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的和不可治愈的肺纤维化。我们推测，碳纳米管由于其特殊的尺寸、大的纵横比和化学组成等独特的性质，可以迅速进入肺内，穿透肺泡上皮屏障，并与肺间质成纤维细胞等特定的肺细胞相互作用，诱导纤维增殖和细胞外基质聚集，这是肺纤维化的特征。我们还认为，这种诱导是通过涉及磷脂酰肌醇-3-激酶(PI3K)/Akt激活和氧化还原调节促纤维化和血管生成因子如转化生长因子-β和血管生成因子的信号级联反应来介导的。在目标1中，我们将确定某些纳米颗粒的特性(例如，直径、长径比、分散状态和化学成分)对碳纳米管诱导的肺纤维化的影响，并开发快速的体外筛选试验，可能预测体内的纤维化反应。目的2将描述CNT诱导纤维化的关键信号通路和致纤维化因素，以确定潜在的诊断和治疗该疾病的生物标志物和药物靶点。目的3探讨血管生成和血管生成因子在碳纳米管诱导的肺纤维化中的作用。目的4研究氧化还原对碳纳米管诱导的肝纤维化和血管生成的调节作用，并阐明其可能的机制。通过这一应用，我们希望确定关键的纳米颗粒特性和一套体外筛选试验，以评估纳米颗粒在体内的潜在致纤维化作用。这些信息对于纳米技术的安全使用将是重要的。拟议的研究还将确定早期发现和治疗纳米材料引起的纤维化肺部疾病的分子靶点。 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和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，因为缺乏能够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美国国立卫生研究院的目标和公共卫生需求：1)确定导致其肺毒性和纤维化的纳米材料的关键物理化学性质；2)开发用于预测纳米材料的纤维化效应的快速筛查方法；3)阐明纳米材料引起肺纤维化的潜在机制，以便为疾病的早期诊断和治疗确定特定的生物标记物和药物靶标。

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.