Nanoparticle Disruption of Cell Function

纳米粒子破坏细胞功能

• 批准号: 7244702
• 负责人: Andrij Holian
• 金额: $ 13.34万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244702
• 关键词: alveolar macrophages; antigen presentation; apoptosis; carbon; cell membrane; confocal scanning microscopy; cytotoxicity; environmental exposure; fluidity; fluorescence microscopy; fluorimetry; free radical oxygen; immune response; immunopathology; inflammation; lipid raft; lung; membrane activity; membrane potentials; nanotechnology; particle; peroxidation; peroxynitrites; phagocytosis; tissue /cell culture

DESCRIPTION (provided by applicant): Carbon nanoparticles (CNPs) are finding increased use in commercial, diagnostic, clinical and other applications. CNP production is anticipated to greatly increase and there is evidence of CNP formation by anthropogenic activity. However, evidence of their potential toxicity is also increasing and respiratory exposure is considered one route of exposure. A number of studies have now demonstrated that manufactured CNP (single walled carbon nanotubes (SWNT), multi-walled carbon nanotubes (MWNT) and to a lesser extent C60 carbon spheres (C60CS)) all cause pulmonary toxicity ranging from inflammation, granuloma formation, fibrosis and airway changes. Macrophages are considered potential targets of CNP in the Jung that may contribute to pathologic outcomes. In vitro toxicity of these particles has been demonstrated with a suggested rank order of potency most often SWNT> MWNT> C60CS. Although reports of nanoparticle toxicity are increasing, the results are often difficult to correlate since the sources (and compositions) and methods of suspension are different for CNP, and often only one particle type is examined. Furthermore, the mechanism(s) by which these uniquely hydrophobic particles are acting is unknown. Based on the unusual physical properties and size of the carbon nanoparticles, as well as our preliminary results with SWNT, MWNT and C60CS, we postulate that CNP are causing membrane disruption leading to changes in macrophage function contributing to lung inflammation. Furthermore, the different sizes of the CNPs may contribute to the rank order of potency and effects. In order to test these hypotheses and gain new information on mechanisms of action we propose the following goals. 1) Compare and evaluate how much variability in biological activity of CNP stems from differences in sources and methods of suspension. 2) Demonstrate that CNP cause alteration of membrane properties and function. 3) Evaluate the effects of CNP on macrophage function related to membrane activity. The results of these studies will provide important new information regarding the roles that different CNP sources, suspension (disaggregation) protocols and CNP types have on membrane disruption. In addition, the studies will provide information on the mechanism of action in membranes how that translates to alterations of macrophage function.

描述（由申请人提供）： 碳纳米粒子 (CNP) 在商业、诊断、临床和其他应用中的应用越来越多。 CNP 的产量预计将大大增加，并且有证据表明 CNP 是由人为活动形成的。然而，其潜在毒性的证据也在增加，呼吸道接触被认为是接触途径之一。许多研究现已证明，制造的 CNP（单壁碳纳米管 (SWNT)、多壁碳纳米管 (MWNT) 以及较小程度的 C60 碳球 (C60CS)）都会引起肺部毒性，包括炎症、肉芽肿形成、纤维化和气道变化。巨噬细胞被认为是 Jung 中 CNP 的潜在靶标，可能有助于病理结果。这些颗粒的体外毒性已通过建议的效力等级顺序得到证实，最常见的是 SWNT > MWNT > C60CS。尽管有关纳米颗粒毒性的报道不断增加，但由于 CNP 的来源（和成分）和悬浮方法不同，而且通常只检查一种颗粒类型，因此结果往往难以关联。此外，这些独特的疏水性颗粒的作用机制尚不清楚。根据碳纳米颗粒不寻常的物理性质和尺寸，以及我们对 SWNT、MWNT 和 C60CS 的初步结果，我们推测 CNP 会导致膜破坏，导致巨噬细胞功能发生变化，从而导致肺部炎症。此外，CNP 的不同大小可能会影响效力和效果的排序。为了检验这些假设并获得有关作用机制的新信息，我们提出以下目标。 1) 比较和评估 CNP 生物活性的差异有多大是由于来源和悬浮方法的差异造成的。 2) 证明CNP引起膜特性和功能的改变。 3)评估CNP对与膜活性相关的巨噬细胞功能的影响。 这些研究的结果将提供关于不同 CNP 来源、悬浮（分解）方案和 CNP 类型对膜破坏的作用的重要新信息。此外，这些研究还将提供有关膜作用机制如何转化为巨噬细胞功能改变的信息。