Pulmonary Innate Immune Modulation by Helical Carbon Nanotubes

描述（由申请人提供）：在环境和职业环境中发现的雾化纳米颗粒易于吸入，并可进入远端气道和肺泡腔，同时避免大多数肺防御和截留机制。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子商业用途，其产量显着增加，对培养物中的多种细胞系显示出显着的细胞毒性和遗传毒性，并且可以在小鼠模型中诱导肺纤维化和炎症以及全身免疫抑制。特别地，碳纳米管和其他纳米颗粒已经显示出抑制巨噬细胞的吞噬作用。然而，还没有进行工作来探索当用肺部感染挑战时纳米管诱导的免疫抑制在模型中的后果。我们的实验室使用铜绿假单胞菌研究宿主/病原体相互作用，铜绿假单胞菌是一种环境和医院病原体，与囊性纤维化、慢性阻塞性肺病、免疫功能低下患者和老年人的严重肺部感染有关。我的项目的首要目标是研究暴露于碳纳米管对宿主响应感染的影响，并确定解释观察到的变化的潜在机制。在本研究中，我将通过关注巨噬细胞功能来研究螺旋碳纳米管（HCNT）慢性暴露后肺部对铜绿假单胞菌感染的免疫反应。我们实验室的早期工作已经证明，在暴露于HCNT后，RAW 264.7巨噬细胞对铜绿假单胞菌的吞噬作用受损，以及小鼠对铜绿假单胞菌感染的急性炎症反应增强。有趣的是，小鼠中铜绿假单胞菌的清除不受先前用HCNT处理的影响，表明肺泡巨噬细胞的吞噬作用在急性免疫应答中起次要作用。本提案旨在确认这一结论。此外，我们将探索在我们的模型中，HCNT是否会损害表面活性蛋白A（SP-A）介导的吞噬作用，因为已经表明纳米管会将蛋白质（包括表面活性蛋白）吸收到其表面上。最后，我们将使用慢性铜绿假单胞菌感染模型来检查HCNT暴露的影响，因为它与肺部炎症、纤维化和清除有关。

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.