Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis

描述（由申请人提供）： 项目摘要：在过去几年中，人造纳米材料的环境和职业接触显著增加，而且随着新纳米材料的生产和各行业的使用越来越多，这一趋势很可能会继续下去。这一趋势引起了极大的关注，因为纳米材料对健康的不利影响相对未知且研究不足。最近的研究表明，肺部暴露于碳纳米管（CNT），工业中最广泛使用的纳米材料之一，导致动物快速和进行性间质性肺纤维化，而不会引起持续性肺部炎症，这通常与其他已知的纤维化药物有关。CNT的这种不寻常的纤维化作用引起了重要的健康问题，因为暴露可能导致致命和不可治愈的肺纤维化。我们假设，CNT，由于其独特的性能，如非常小的尺寸，大的纵横比，和化学成分可以迅速进入肺，穿透肺泡上皮屏障，并与特定的肺细胞，如间质肺成纤维细胞相互作用，以诱导纤维增生和细胞外基质积累，这是肺纤维化的特征。我们还提出，这种诱导是由信号级联介导的，涉及磷脂酰肌醇-3-激酶（PI 3 K）/Akt激活和氧化还原调节促纤维化和血管生成因子，如TGF-β和VEGF。在目标1中，我们将确定某些纳米颗粒特性（例如，直径、纵横比、分散状态和化学）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。目的2将描述CNT诱导纤维化的关键信号通路和纤维化因子，以确定诊断和治疗该疾病的潜在生物标志物和药物靶点。目的3探讨血管生成及血管生成因子在碳纳米管致肺纤维化中的作用。目的4研究CNT诱导的纤维化和血管生成的氧化还原调控机制，并阐明其机制。通过这一应用，我们期望定义关键的纳米颗粒特性和一组体外筛选试验，用于评估纳米颗粒在体内的潜在致纤维化性。这些信息对于安全使用纳米技术将是重要的。拟议的研究还将确定早期检测和治疗纳米材料引起的纤维化肺病的分子靶点。 公共卫生相关性： 与公共卫生的相关性：纳米技术提供了巨大的机会，创造新的和更好的产品，用于工业应用和诊断和治疗疾病。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解决NIH目标和公共卫生需求：1）确定纳米材料导致其肺毒性和纤维化的关键理化特性，2）开发快速筛选测定方法，用于预测纳米材料的纤维化效应，和3）阐明纳米材料诱导肺纤维化的潜在机制，以确定用于早期诊断的特定生物标志物和药物靶点，疾病的治疗。

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.