Nano-Bio Interactions at the Surface of Pulmonary Surfactant Films

随着纳米技术的快速发展和纳米消费品的广泛扩散，人们越来越关注纳米颗粒(NPs)对环境、健康和安全(EHS)的潜在不利影响，纳米颗粒的特征尺寸小于100 nm。大多数NPs都很轻，而且是可呼吸的。一旦吸入，NPs就会渗透到肺部，干扰呼吸功能。肺的整个表面都覆盖着一层脂质蛋白肺表面活性物质(PS)膜，它具有重要的生理功能，即宿主防御和降低表面张力。因此，吸入的纳米粒子与PS膜之间的相互作用代表了肺部最初的纳米生物现象。这种相互作用决定了吸入的NPs的命运及其潜在的治疗或毒理作用。这项建议将利用PI实验室开发的新的实验和计算技术来研究NP-PS相互作用的详细机制。这些技术可以高保真地模拟空气污染的场景，在这种场景中，NPs被吸入并沉积在PS膜的表面。利用这些模型系统，将彻底评估含NP的喷雾剂和涂料等NPs和纳米产品的潜在环境危害。该倡议将特别侧重于研究可呼吸NPs对婴儿和儿童的潜在风险，这些婴儿和儿童脆弱的呼吸系统使他们比成年人更容易受到NP的影响。拟议的研究将有助于为管理和监督纳米技术的商业应用提供一个有用的衡量标准，以实现更安全和可持续的发展。这项建议的研究目标是研究空气中工程纳米颗粒(NPs)与天然肺表面活性物质(PS)相互作用的详细生物物理化学机制。由于以下两个主要视角，这项研究具有很高的新颖性。首先，将使用多尺度体外和电子模拟相结合的方法来研究NP-PS相互作用。这项体外研究依赖于生物物理模拟，使用了PI实验室最近开发的一种新的实验方法。有了这个体外模型，PS膜上的纳米生物相互作用将被完全控制的NP气溶胶剂量学模拟，并在生理相关的呼吸条件下进行。这项电子研究依赖于高保真的分子动力学模拟，它允许探索NP跨PS膜转移的详细分子机制。其次，PI将对与NPs接触肺液的生物分子日冕进行首次全面研究，即所谓的PS生物分子日冕。通过相关的高精度质谱学和分子动力学模拟，该项目将以前所未有的细节揭示PS生物分子日冕的生化组成和生物物理构象。这项研究有望显著推进目前对呼吸系统中纳米生物相互作用的理解，并为纳米技术对EHS的影响提供新的见解。这项提议的更广泛的影响是丰富和多样的。该方案中开发的体外和硅胶模拟是探索纳米技术对EHS影响的经济有效的手段。这项拟议的研究将补充目前从细胞培养和动物模型中获得的纳米毒理学知识。本研究揭示的生物物理化学机制对于设计基于NP的肺部给药和更好地理解与空气污染和颗粒物伤害相关的呼吸系统疾病的病理生理学具有明显的变革价值。在与当地医疗保健提供者的合作下，该协会致力于提高公众对婴儿和儿童呼吸性NPs潜在风险的认识。鉴于夏威夷大学的独特地理位置，国际和平协会致力于促进夏威夷原住民、太平洋岛民以及来自其他代表性不足群体和低收入家庭的学生的参与。PI还将开发具有跨学科组成部分的本科生和研究生工程课程，并帮助加强研究和教育的基础设施。

PI: Zuo, Yi#1604119The rapid development of nanotechnology and a widespread proliferation of nano-enabled consumer products post an increasing concern of the potential adverse environment, health, and safety (EHS) impacts of nanoparticles (NPs), which feature a characteristic size less than 100 nm. Most NPs are lightweight and respirable. Once inhaled, NPs can penetrate into the lungs and interfere with the respiratory function. The entire surface of the lungs is lined with a lipid-protein pulmonary surfactant (PS) film which serves an important physiological function of host defense and surface tension reduction. Interactions between inhaled NPs and the PS film hence represent the initial nano-bio phenomena in the lungs. Such interactions determine the fate of the inhaled NPs and their potential therapeutic or toxicological effects. This proposal will investigate the detailed mechanism of NP-PS interactions using novel experimental and computational techniques developed in the PI's laboratory. These techniques allow high-fidelity simulations of air pollution scenarios in which NPs are inhaled and deposited at the surface of the PS film. Using these model systems, potential environmental hazards of NPs and nano-enabled products, such as NP-containing sprays and paints, will be thoroughly evaluated. The PI will specifically focus on studying the potential risk of respirable NPs for infants and children whose fragile respiratory system makes them more vulnerable to NP exposure than adults. The proposed study will help provide a useful metric for regulating and overseeing commercial applications of nanotechnology towards a safer and sustainable development. The research goal of this proposal is to study the detailed biophysicochemical mechanisms by which airborne engineered nanoparticles (NPs) interact with natural pulmonary surfactant (PS). This research is highly novel due to the following two main perspectives. First, NP-PS interactions will be studied using a combined approach of multiscale in vitro and in silico simulations. The in vitro study relies on biophysical simulations using a novel experimental methodology recently developed in the PI's laboratory. With this in vitro model, nano-bio interactions at the PS film will be mimicked with fully controlled NP aerosol dosimetry and under physiologically relevant respiratory conditions. The in silico study relies on high-fidelity molecular dynamics simulations which allow probing the detailed molecular mechanism of NP translocation across the PS film. Second, the PI will carry out the first comprehensive study of the biomolecular corona bound to NPs in contact with lung fluids, i.e., the so-called PS biomolecular corona. With correlated high-precision mass spectrometry and molecular dynamics simulations, the proposed project will reveal the biochemical composition and biophysical conformation of the PS biomolecular corona with unprecedented details. This research is expected to significantly advance current understanding of nano-bio interactions in the respiratory system and to provide novel insight into the EHS impacts of nanotechnology.The broader impacts of this proposal are rich and multifarious. In vitro and in silico simulations developed in this proposal are cost-effective means of exploring the EHS impacts of nanotechnology. The proposed study will complement the current nanotoxicological knowledge obtained from cell culture and animal-models. The biophysicochemical mechanism revealed by this study has clear transformative values for designing NP-based pulmonary drug delivery and for better understanding the pathophysiology of respiratory diseases related to air pollution and particle insult. In collaboration with local healthcare providers, the PI is engaged in activities of increasing the public awareness of the potential risk of respirable NPs for infants and children. Given the unique location of the University of Hawaii, the PI is dedicated to promoting participation of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups and low-income families. The PI will also develop undergraduate and graduate engineering curricula with interdisciplinary components, and help enhance the infrastructure for research and education.