Environmental and occupational exposures to manufactured nanomaterials have markedly increased during the past recent years, and in all likelihood this trend will continue as new nanomaterials are being increasingly produced and used by various industries. This trend has been of great concern as the adverse health effects of nanomaterials are relatively unknown and understudied. Recent studies have shown that pulmonary exposure to carbon nanotubes (CNT), one of the most widely used nanomaterials in industry, results in rapid and progressive interstitial lung fibrosis in animals without causing persistent lung inflammation, which is normally associated with other known fibrogenic agents. This unusual fibrogenic effect of CNT raises important health issues since the exposure could result in deadly and incurable lung fibrosis. We hypothesize that CNT, due to their unique properties such as exceptionally small size, large aspect ratio, and chemical composition can rapidly enter the lung, penetrate the alveolar epithelial barrier, and interact with specific lung cells such as interstitial lung fibroblasts to induce fibroproliferation and extracellular matrix accumulation, which are characteristics of lung fibrosis. We also propose that such induction is mediated by signaling cascades that involve phosphatidylinositol-3-kinase(PI3K)/Akt activation and redox regulation of the profibrogenic and angiogenic factors such as TGF-b and VEGF.
In Aim 1, we will determine the impact of certain nanoparticle characteristics (e.g., diameter, aspect ratio, dispersion status, and chemistry) on CNT-induced lung fibrosis and develop rapid in vitro screening assays which may be predictive of the in vivo fibrogenic response.
Aim 2 will delineate key signaling pathways and fibrogenic factors involved in the induction of fibrosis by CNT in order to identify potential biomarkers and drug targets for diagnosis and treatment of the disease.
Aim 3 will investigate the involvement of angiogenesis and angiogenic factors in the development of pulmonary fibrosis induced by CNT.
Aim 4 will determine redox regulation of CNT-induced fibrogenesis and angiogenesis and elucidate the underlying mechanisms. Through this application, we expect to define key nanoparticle characteristics and a set of in vitro screening assays for evaluation of the potential fibrogenicity of nanoparticles in vivo. Such information will be important for safe use of nanotechnology. The proposed studies will also identify molecular targets for early detection and treatment of fibrotic lung diseases caused by nanomaterials.

Public Health Relevance

Relevance to Public Health: Nanotechnology presents enormous opportunities to create new and better products for industrial applications and for diagnosis and treatment of diseases. However, the potential adverse health effects of nanomaterials are unclear since information is lacking that would allow prediction of the biological activity of these new materials. This project will address NIH goals and public health needs by 1) determining key physiochemical properties of nanomaterials that contribute to their pulmonary toxicity and fibrogenicity, 2) developing rapid screening assays for prediction of the fibrogenic effects of nanomaterials, and 3) elucidating the underlying mechanisms of pulmonary fibrosis induced by nanomaterials in order to identify specific biomarkers and drug targets for early diagnosis and treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095579-03
Application #
8268403
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Eu, Jerry Pc
Project Start
2010-07-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$366,300
Indirect Cost
$118,800
Name
West Virginia University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Mishra, Anurag; Stueckle, Todd A; Mercer, Robert R et al. (2015) Identification of TGF-β receptor-1 as a key regulator of carbon nanotube-induced fibrogenesis. Am J Physiol Lung Cell Mol Physiol 309:L821-33
Pongrakhananon, Varisa; Luanpitpong, Sudjit; Stueckle, Todd A et al. (2015) Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein. Toxicol Sci 143:499-511
Luanpitpong, Sudjit; Wang, Liying; Castranova, Vincent et al. (2014) Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes. Part Fibre Toxicol 11:22
Luanpitpong, Sudjit; Chen, Michael; Knuckles, Travis et al. (2014) Appalachian mountaintop mining particulate matter induces neoplastic transformation of human bronchial epithelial cells and promotes tumor formation. Environ Sci Technol 48:12912-9
Wang, Liying; Stueckle, Todd A; Mishra, Anurag et al. (2014) Neoplastic-like transformation effect of single-walled and multi-walled carbon nanotubes compared to asbestos on human lung small airway epithelial cells. Nanotoxicology 8:485-507
Lohcharoenkal, Warangkana; Wang, Liying; Stueckle, Todd A et al. (2014) Role of H-Ras/ERK signaling in carbon nanotube-induced neoplastic-like transformation of human mesothelial cells. Front Physiol 5:222
Luanpitpong, Sudjit; Wang, Liying; Manke, Amruta et al. (2014) Induction of stemlike cells with fibrogenic properties by carbon nanotubes and its role in fibrogenesis. Nano Lett 14:3110-6
Luanpitpong, Sudjit; Wang, Liying; Rojanasakul, Yon (2014) The effects of carbon nanotubes on lung and dermal cellular behaviors. Nanomedicine (Lond) 9:895-912
Manke, Amruta; Luanpitpong, Sudjit; Rojanasakul, Yon (2014) Potential Occupational Risks Associated with Pulmonary Toxicity of Carbon Nanotubes. Occup Med Health Aff 2:
Talbott, Siera Jo; Luanpitpong, Sudjit; Stehlik, Christian et al. (2014) S-nitrosylation of FLICE inhibitory protein determines its interaction with RIP1 and activation of NF-κB. Cell Cycle 13:1948-57

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