Pulmonary Innate Immune Modulation by Helical Carbon Nanotubes

螺旋碳纳米管对肺部先天免疫的调节

• 批准号: 8525846
• 负责人: Brent Walling
• 金额: $ 6.2万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525846
• 关键词: A Mouse; Acute; Adverse effects; Affect; Alveolar; Alveolar Macrophages; Bacteria; Binding; Biological; Bleomycin; Breathing; Bypass; Carbon Nanotubes; Cell Line; Chronic; Chronic Obstructive Airway Disease; Clinical; Cystic Fibrosis; Distal; Elderly; Electronics; Environment; Environmental Health; Environmental and Occupational Exposure; Epithelial Cells; Exposure to; Fibrosis; Goals; Immune; Immune response; Immunocompromised Host; Immunosuppression; Individual; Infection; Inflammatory Response; Label; Laboratories; Link; Lung; Mediating; Minor; Mission; Modeling; Monoclonal Antibodies; Mus; Nanotubes; Natural Immunity; Occupational; Occupational Health; Pathway interactions; Phagocytosis; Phagocytosis Inhibition; Play; Pneumonia; Production; Proteins; Pseudomonas; Pseudomonas aeruginosa; Pulmonary Fibrosis; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Proteins; Risk; Role; Surface; Technology; Time; Toxic effect; Travel; United States National Institutes of Health; Western Blotting; Work; aerosolized; antimicrobial; burden of illness; commercial application; cytotoxicity; genotoxicity; immune clearance; immunoregulation; macrophage; man; mouse model; nanoparticulate; neutrophil; pathogen; public health relevance; receptor; research study; respiratory; response; surfactant

DESCRIPTION (provided by applicant): Aerosolized nanoparticulates, found both in the environment and occupational settings, are readily inhaled and can travel to the distal airways and alveolar spaces while avoiding most of the pulmonary defense and entrapment mechanisms. Carbon nanotubes, a relatively new nanoparticulate which has seen a marked increase in production due to multiple potential biomedical and electrical commercial uses, has shown significant cytotoxicity and genotoxocity towards multiple cell lines in culture and can induce pulmonary fibrosis and inflammation in mouse models as well as systemic immune suppression. In particular, carbon nanotubes and other nanoparticulates have been shown to inhibit phagocytosis by macrophages. However, no work has been performed to explore the consequences of nanotube induced immune suppression in models when challenged with a pulmonary infection. Our laboratory investigates the host/pathogen interaction using Pseudomonas aeuruginosa, an environmental and nosocomial pathogen which has been linked to severe pulmonary infections in individuals with cystic fibrosis, chronic obstructive pulmonary disease, immunocompromised patients, and the elderly. The overarching goal of my project is to examine the impact that exposure to carbon nanotubes has on the host in response to infection by P. aeuruginosa and determine the underlying mechanisms to explain observed changes. In this proposal, I will investigate the pulmonary immune response to infection by P. aeuruginosa following chronic exposure to helical carbon nanotubes (HCNT) by focusing on the macrophage function. Early work in our lab has demonstrated impaired phagocytosis of P. aeuruginosa by RAW 264.7 macrophages following exposure to HCNTs as well as an enhanced acute inflammatory response to P. aeuruginosa infection in mice. Interestingly, clearance of P. aeuruginosa in mice was not affected by prior treatment with HCNTs, suggesting that phagocytosis by alveolar macrophages plays a minor role in the acute immune response. This proposal seeks to confirm this finding. Additionally, we will be exploring whether HCNTs impair surfactant protein A (SP-A) mediated phagocytosis in our models as it has been shown that nanotubes will absorb proteins, including the surfactant proteins, onto their surface. Finally, we will be using a chronic P. aeuruginosa infection model to examine the impact of HCNT exposure as it relates to pulmonary inflammation, fibrosis, and clearance.

描述（由申请人提供）：雾化纳米颗粒，在环境和职业环境中都可以发现，很容易被吸入，可以到达远端气道和肺泡间隙，同时避免大多数肺防御和夹持机制。碳纳米管是一种相对较新的纳米颗粒，由于多种潜在的生物医学和电气商业用途，其产量显著增加，在培养过程中对多种细胞系显示出显著的细胞毒性和基因毒性，并可在小鼠模型中诱导肺纤维化和炎症以及全身免疫抑制。特别是，碳纳米管和其他纳米颗粒已被证明可以抑制巨噬细胞的吞噬作用。然而，目前还没有研究在肺部感染时纳米管诱导的模型免疫抑制的后果。我们的实验室使用绿脓杆菌研究宿主/病原体相互作用，绿脓杆菌是一种环境和医院病原体，与囊性纤维化、慢性阻塞性肺疾病、免疫功能低下患者和老年人的严重肺部感染有关。我项目的首要目标是研究暴露于碳纳米管对宿主对绿脓杆菌感染的影响，并确定解释观察到的变化的潜在机制。在本提案中，我将通过关注巨噬细胞功能来研究慢性暴露于螺旋碳纳米管（HCNT）后肺对绿脓杆菌感染的免疫反应。我们实验室的早期工作证明，暴露于HCNTs后，RAW 264.7巨噬细胞对假单胞菌的吞噬能力受损，小鼠对假单胞菌感染的急性炎症反应增强。有趣的是，小鼠对假单胞菌的清除不受先前用HCNTs治疗的影响，这表明肺泡巨噬细胞的吞噬作用在急性免疫反应中起次要作用。本提案旨在证实这一发现。此外，我们将在我们的模型中探索HCNTs是否会损害表面活性剂蛋白A （SP-A）介导的吞噬作用，因为已有研究表明，纳米管会将蛋白质（包括表面活性剂蛋白）吸收到其表面。最后，我们将使用慢性假单胞菌感染模型来检查HCNT暴露对肺部炎症、纤维化和清除的影响。