Pulmonary Innate Immune Modulation by Helical Carbon Nanotubes

描述(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，并可以进入远端呼吸道和肺泡腔，同时避免了大多数肺防御和困住机制。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，其产量已显著增加，在培养的多个细胞系中显示出显著的细胞毒性和遗传毒性，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经被证明可以抑制巨噬细胞的吞噬作用。然而，还没有开展工作来探索当受到肺部感染时，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Euruginosa假单胞菌研究宿主/病原体的相互作用，这种环境和医院病原体与囊性纤维化、慢性阻塞性肺疾病、免疫功能低下的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检查暴露在碳纳米管中对宿主应对金黄色葡萄球菌感染的影响，并确定解释观察到的变化的潜在机制。在这项建议中，我将通过重点研究巨噬细胞功能来研究慢性暴露于螺旋碳纳米管(HCNT)后，肺部对金黄色葡萄球菌感染的免疫反应。我们实验室的早期工作表明，暴露于HCNTs后，RAW 264.7巨噬细胞对金黄色葡萄球菌的吞噬功能受损，小鼠对金黄色葡萄球菌感染的急性炎症反应增强。有趣的是，小鼠对金黄色葡萄球菌的清除不受HCNTs预先处理的影响，这表明肺泡巨噬细胞的吞噬作用在急性免疫反应中起着较小的作用。这项提议试图证实这一发现。此外，在我们的模型中，我们将探索碳纳米管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，纳米管将吸收蛋白质，包括表面活性蛋白质，到它们的表面。最后，我们将使用一个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.