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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
High Impact Research and Research Infrastructure Programs (RC2)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-SET-V (04))
Program Officer
Nadadur, Srikanth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
Zip Code
Xia, Tian; Hamilton, Raymond F; Bonner, James C et al. (2013) Interlaboratory evaluation of in vitro cytotoxicity and inflammatory responses to engineered nanomaterials: the NIEHS Nano GO Consortium. Environ Health Perspect 121:683-90
Fazlollahi, Farnoosh; Kim, Yong Ho; Sipos, Arnold et al. (2013) Nanoparticle translocation across mouse alveolar epithelial cell monolayers: species-specific mechanisms. Nanomedicine 9:786-94
Negoda, Alexander; Kim, Kwang-Jin; Crandall, Edward D et al. (2013) Polystyrene nanoparticle exposure induces ion-selective pores in lipid bilayers. Biochim Biophys Acta 1828:2215-22
Zhou, Beiyun; Liu, Yixin; Kahn, Michael et al. (2012) Interactions between ?-catenin and transforming growth factor-? signaling pathways mediate epithelial-mesenchymal transition and are dependent on the transcriptional co-activator cAMP-response element-binding protein (CREB)-binding protein (CBP). J Biol Chem 287:7026-38
DeMaio, Lucas; Buckley, Stephen T; Krishnaveni, Manda S et al. (2012) Ligand-independent transforming growth factor-? type I receptor signalling mediates type I collagen-induced epithelial-mesenchymal transition. J Pathol 226:633-44
Zhou, Beiyun; Buckley, Stephen T; Patel, Vipul et al. (2012) Troglitazone attenuates TGF-ýý1-induced EMT in alveolar epithelial cells via a PPARýý-independent mechanism. PLoS One 7:e38827
Yacobi, Nazanin R; Fazllolahi, Farnoosh; Kim, Yong Ho et al. (2011) Nanomaterial interactions with and trafficking across the lung alveolar epithelial barrier: implications for health effects of air-pollution particles. Air Qual Atmos Health 4:65-78
Fazlollahi, Farnoosh; Sipos, Arnold; Kim, Yong Ho et al. (2011) Translocation of PEGylated quantum dots across rat alveolar epithelial cell monolayers. Int J Nanomedicine 6:2849-57
Fazlollahi, Farnoosh; Angelow, Susanne; Yacobi, Nazanin R et al. (2011) Polystyrene nanoparticle trafficking across MDCK-II. Nanomedicine 7:588-94
Zhong, Qian; Zhou, Beiyun; Ann, David K et al. (2011) Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol 45:498-509

Showing the most recent 10 out of 12 publications