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Prediction and Mechanism of Carbon Nanotube-Induced Fibrosis

碳纳米管诱导纤维化的预测及机制

基本信息

批准号：
8463235
负责人：
Yon Rojanasakul
金额：
$ 34.87万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463235
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 Targeting 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 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 screening single walled carbon nanotube trend

项目摘要

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.

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，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积累，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点。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Carbon nanotubes induce malignant transformation and tumorigenesis of human lung epithelial cells.

DOI：
10.1021/nl2011214
发表时间：
2011-07-13
期刊：
Nano letters
影响因子：
10.8
作者：
Wang L;Luanpitpong S;Castranova V;Tse W;Lu Y;Pongrakhananon V;Rojanasakul Y
通讯作者：
Rojanasakul Y

Dispersion of single-walled carbon nanotubes by a natural lung surfactant for pulmonary in vitro and in vivo toxicity studies.

DOI：
10.1186/1743-8977-7-31
发表时间：
2010-10-19
期刊：
Particle and fibre toxicology
影响因子：
10
作者：
Wang L;Castranova V;Mishra A;Chen B;Mercer RR;Schwegler-Berry D;Rojanasakul Y
通讯作者：
Rojanasakul Y

Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein.

碳纳米管通过FLICE抑制蛋白诱导人肺上皮细胞凋亡抵抗。

DOI：
10.1093/toxsci/kfu251
发表时间：
2015
期刊：
Toxicological sciences : an official journal of the Society of Toxicology
影响因子：
0
作者：
Pongrakhananon,Varisa;Luanpitpong,Sudjit;Stueckle,ToddA;Wang,Liying;Nimmannit,Ubonthip;Rojanasakul,Yon
通讯作者：
Rojanasakul,Yon

Reactive oxygen species-mediated p38 MAPK regulates carbon nanotube-induced fibrogenic and angiogenic responses.