Inhalation of ultrafine (nano)particles has been associated with adverse cardiovascular, pulmonary and hematologic effects, localization of particles in blood vessels and end organs, and increased morbidity and mortality in susceptible populations. Since the particles are inhaled, their most likely route of entry into the systemic circulation is across the alveolar epithelium of the lung. Although utilization of nanoparticles due to expansion of the science and application of nanotechnology is expected to markedly increase, the mechanisms by which nanoparticles injure and/or are transported into/across alveolar epithelium are not well known. Based on our preliminary data on lung injury/uptake/trafficking of several classes of nanoparticles (composed of polystyrene, silica and metal (oxides)) with defined physicochemical characteristics and recent reports on health effects of inhaled ultrafine air pollutant particulates, we hypothesize that interactions between nanoparticles and alveolar epithelial cells i) can disrupt normal alveolar epithelial cell homeostasis and induce changes in cellular properties and alveolar epithelial barrier function, ii) provide the primary portal of entry for nanoparticles into the systemic circulation via transepithelial translocation pathways, and iii) are highly dependent on physicochemical properties of the nanoparticles. Utilizing defined polystyrene, silica and metal (oxide) nanoparticles in in vitro models (including our well-established primary cultured monolayers of rat or human alveolar epithelial cells) and rat lungs in vivo, we will test these hypotheses by investigating the following four major aims: 1) nanoparticle effects on active and passive barrier properties of alveolar epithelium;2) internalization, fate and effects of nanoparticles in alveolar epithelial cells;3) trafficking of nanoparticles across alveolar epithelium in vitro;and 4) nanoparticle internalization and trafficking in rat lungs in vivo, correlating injury to/uptake into/trafficking across distal respiratory epithelium in vivo vs in vitro. In addition, we will utilize simplified models of artificial lipid bilayers reconstituted on permeable filters and giant unilamellar vesicles to determine the role(s) of passive mechanisms (e.g., diffusion) and/or disruption of lipid bilayers in nanoparticle entry into/exit from alveolar epithelial cells. Findings from the investigations proposed herein will provide insights into cytotoxicity and mechanisms of internalization/trafficking of nanoparticles with defined physicochemical properties into/across the lung alveolar epithelium. Our major objective is to obtain new information on nanoparticle interactions with alveolar epithelium in order to help understand effects on the lung of inhaled manufactured nanoparticles and environmental air pollutant ultrafine particulates, point directions for management of resultant deleterious effects, and lead to improved design of defined nanoparticles for safer and more efficient biomedical applications (e.g., pulmonary drug/gene delivery).

Public Health Relevance

Inhalation of ultrafine ambient pollutant particles (<100 nm) may be associated with adverse cardiovascular and pulmonary effects, resulting in increased morbidity and mortality in susceptible populations. The mechanisms by which these nanoparticles injure and/or are transported into/across alveolar epithelium lining distal airspaces of the lung are not well understood, although it is known that they can affect barrier properties of alveolar epithelium and be internalized by/translocated across alveolar epithelial cells. We will use three classes of defined nanoparticles (comprised of polystyrene, silica or metal (oxide)) to determine interactions with both in vitro and in vivo models of the alveolar barrier in order to help prevent injury from inhaled nanoparticles and design nanoparticles for biological applications (e.g., drug/gene delivery).

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES017034-04
Application #
8249083
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Nadadur, Srikanth
Project Start
2009-06-15
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$357,247
Indirect Cost
$136,724
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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