Interactions of engineered nanomaterials with lung alveolar epithelium

工程纳米材料与肺泡上皮的相互作用

• 批准号: 7852903
• 负责人: EDWARD DAVID CRANDALL
• 金额: $ 40万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852903
• 关键词: Adherent Culture; Air Pollutants; Air Pollution; Alveolar; Apical; Biological; Blood; Blood Circulation; Blood-Air Barrier; Breathing; Caliber; Carbon; Carbon Nanotubes; Carbon nanoparticle; Cardiovascular system; Cell physiology; Cells; Characteristics; Charge; Classification; Data; Distal; Edema; Engineering; Epithelial; Epithelial Cells; Exposure to; Fullerenes; Future; Gases; Gene Delivery; Health; Heart; Homeostasis; Hydrophobicity; In Vitro; Inflammation; Injury; Investigation; Ion Transport; Knowledge; Lipids; Love; Lung; Metals; Modeling; Morbidity - disease rate; Nanotechnology; Nanotubes; Organ; Particulate; Pathway interactions; Pharmaceutical Preparations; Polystyrenes; Population; Property; Quantum Dots; Rattus; Regulation; Reporting; Research; Route; Science; Shapes; Silicon Dioxide; Structure of respiratory epithelium; Surface; Surface Properties; Technology; Testing; Thrombosis; Tissues; Toxic effect; Ultrafine; Water; alveolar epithelium; alveolar homeostasis; ambient particle; atherogenesis; base; bioimaging; cytotoxicity; design; improved; in vitro Model; in vivo; injured; insight; interest; lung injury; metal oxide; mortality; nanomaterials; nanoparticle; nanoscale; particle; pollutant; public health relevance; rapid growth; trafficking; ultrafine particle; uptake

DESCRIPTION (provided by applicant): Although utilization of engineered nanomaterials (ENM) due to expansion of the science and application of nanobiomedicine/technology is expected to markedly increase, the mechanisms by which ENM injure and/or are transported into/across lung alveolar epithelium are not well known. Inhalation of ambient ultrafine particulates (whose size range overlaps the current definition of nanomaterials) has been shown to result in adverse cardiovascular, pulmonary and hematologic effects. If any ENM are accidently inhaled, their most likely route of entry into the systemic circulation is across the alveolar epithelium of the lung. Based on our ongoing research on lung injury and trafficking of several (e.g., polystyrene, silica and metal (oxides)) classes of nanoparticles with defined physicochemical characteristics, and recent reports on health effects of inhaled ultrafine air pollutant particulates and other nanomaterials (especially fullerenes and their derivatives), we hypothesize that interactions between various forms of ENM (e.g., negative vs. positive fullerenes; pristine (hydrophobic) vs. derivatized (hydrophilic) fullerenes; fullerenes of different mass (e.g., C60, C70, vs. C80 vs. polymeric fullerenes) and alveolar epithelial cells i) can disrupt normal alveolar epithelial cell homeostasis and induce changes in cellular properties and alveolar epithelial barrier function in an ENM-specific manner, ii) can provide the primary portal of entry for ENM into the systemic circulation (e.g., fullerenes may be translocated via transepithelial translocation pathways), and iii) are highly dependent on physicochemical properties of ENM (e.g., fullerenes). Utilizing fullerenes of appropriately modified surface characteristics in in vitro models (including our well-established primary cultured monolayers of rat alveolar epithelial cells) and rat lungs in vivo, we will test these hypotheses by investigating the following four aims: 1) effects of apically exposing fullerenes on active and passive barrier properties of alveolar epithelium in vitro; 2) internalization, fate and effects of fullerenes in alveolar epithelial cells in vitro; 3) trafficking of fullerenes across alveolar epithelium in vitro; and 4) fullerene internalization and trafficking in rat lungs in vivo, correlating injury to and trafficking across distal respiratory epithelium in vivo vs. in vitro. Findings from the investigations proposed herein will provide insights into cytotoxicity and mechanisms of internalization/trafficking of fullerenes with defined physicochemical properties into/across lung alveolar epithelium. Our major objective is to obtain new information on fullerene (and other ENM) interactions with alveolar epithelium in order to help understand interactions with the lung, and help improve future nanobiomedical applications (e.g., pulmonary drug/gene delivery). PUBLIC HEALTH RELEVANCE: Inhalation of man-made nanomaterials (<100 nm in diameter), including ultrafine ambient pollutant particles and engineered/manufactured nanomaterials (ENM: examples are fullerenes (composed of >60 carbon atoms), carbon nanotubes (CNT), quantum dots and metal /metal oxide nanoparticles), may be associated with various heart-, blood- and lung-related health effects. It appears that these effects may increase morbidity and mortality in susceptible populations. Of these nanomaterials, fullerenes have been manufactured in an astonishingly large quantity for wide applications, yet the mechanisms by which this particular ENM (e.g., fullerenes with positive vs. negative surface charges and/or pristine (lipid-loving) vs. derivatized (water-loving)) injure and/or are translocated into and/or across alveolar epithelium (where gas exchange and ion transport occur in the distal portion of the lung) are not well understood. We will determine interactions with both in vitro and in vivo rat models of the distal air-blood barrier of the lung (i.e., alveolar epithelium) in order to help understand possible injury from inhaled fullerenes with defined surface properties (e.g., charge and hydrophobicity). With this knowledge, improved nanomedical and biological applications (e.g., drug/gene delivery) using fullerenes bearing specific surface properties (that do not cause injury) can be designed for future applications.

描述（由申请人提供）：尽管由于纳米生物医学/技术的科学和应用的扩展，工程纳米材料（ENM）的利用预计将显著增加，但ENM损伤和/或转运进入/穿过肺泡上皮的机制尚不清楚。吸入环境超细颗粒物（其尺寸范围与纳米材料的当前定义重叠）已被证明会导致心血管、肺和血液学方面的不良影响。如果意外吸入任何ENM，它们进入体循环的最可能途径是穿过肺的肺泡上皮。根据我们正在进行的关于肺损伤和贩运几种（例如，聚苯乙烯、二氧化硅和金属（氧化物））类的具有确定的物理化学特性的纳米颗粒，以及最近关于吸入的超细空气污染物颗粒和其他纳米材料（特别是富勒烯及其衍生物）对健康影响的报道，我们假设各种形式的ENM（例如，负富勒烯对正富勒烯;原始（疏水）富勒烯对衍生（亲水）富勒烯;不同质量的富勒烯（例如，C60、C70、相对于C80、相对于聚合富勒烯）和肺泡上皮细胞i）可以破坏正常的肺泡上皮细胞稳态并以ENM特异性方式诱导细胞特性和肺泡上皮屏障功能的变化，ii）可以提供ENM进入体循环的主要入口（例如，富勒烯可以通过跨上皮易位途径易位），和iii）高度依赖于ENM的物理化学性质（例如，富勒烯）。在体外模型中利用适当修饰表面特性的富勒烯本研究通过对大鼠肺泡上皮细胞（包括我们建立的大鼠肺泡上皮细胞原代单层培养）和大鼠肺的体外实验，通过以下四个方面的研究来验证这些假设：1）顶暴露富勒烯对体外肺泡上皮细胞主动和被动屏障特性的影响;（2）富勒烯在肺泡上皮细胞内的内化、归宿和作用：（3）富勒烯在肺泡上皮细胞内的转运;以及4）富勒烯在体内大鼠肺中的内化和运输，将体内与体外的损伤和穿过远端呼吸上皮的运输相关联。本文提出的调查结果将提供深入了解细胞毒性和机制的内化/贩运的富勒烯定义的理化性质进入/穿过肺泡上皮细胞。我们的主要目标是获得关于富勒烯（和其他ENM）与肺泡上皮相互作用的新信息，以帮助理解与肺的相互作用，并帮助改善未来的纳米生物医学应用（例如，肺部药物/基因递送）。 公共卫生相关性：吸入人造纳米材料（直径<100 nm），包括超细环境污染物颗粒和工程/人造纳米材料（ENM：例如富勒烯（由>60个碳原子组成）、碳纳米管（CNT）、量子点和金属/金属氧化物纳米颗粒），可能与各种心脏、血液和肺相关的健康影响有关。这些影响可能会增加易感人群的发病率和死亡率。在这些纳米材料中，富勒烯已经被大量制造用于广泛的应用，但是这种特定的ENM（例如，具有正表面电荷与负表面电荷和/或原始（亲脂）与衍生（亲水）的富勒烯）损伤和/或移位进入和/或穿过肺泡上皮（其中气体交换和离子运输发生在肺的远端部分）还没有很好地理解。我们将确定与肺远端空气-血液屏障的体外和体内大鼠模型的相互作用（即，肺泡上皮）以帮助理解吸入的具有确定表面性质的富勒烯可能造成的损伤（例如，电荷和疏水性）。有了这些知识，改进的纳米医学和生物学应用（例如，药物/基因递送），可以设计用于未来的应用。