Carbon nanotubes exhibit exceptional structural properties and conductivity, and are being incorporated into diverse manufacturing processes, yet little is known about the risks that these novel molecules pose to human health. Emerging observations indicate that pulmonary exposure to carbon nanotubes induce a fibrotic response in the lungs that is related at least in part due to their size and shape. Preliminary experiments from our group indicate that pulmonary exposure to multiwalled carbon nanotubes (MWCNT) alters hemostasis, vascular reactivity, and myocardial injury resulting from acute coronary occulusion and reperfusion. Furthermore, comparison to other nano-scale particles, including elemental carbon (Printex 90), ceramic nanoparticles and ambient particulate matter, indicates that cardiotoxicity of nano-scale particles is related more to the particle composition and surface characteristics than to its shape. In this project, we propose to test the hypothesis that respirable MWCNT are cardiotoxic, and how MWCNTtissue interaction impacts their biological activity. MWCNT of uniform length (10 to 20 |am) and well-defined surface characteristics will be generated through a collaboration with the Institute of Regenerative Medicine at Winston-Salem Health Sciences Center and NanoTechLabs, Inc. Investigators at the East Carolina University will deliver the nanotubes by acute inhalation to mice, verify the pulmonary distribution and define the acute and chronic effects of particle exposure on hemostasis, vascular reactivity, and myocardial response to ischemia. The modifications to be compared represent alteration to the pristine MWCNT and surface functionalization paradigms that are common in nanotechnology and will include a) nitrogen-doping, b) surface carboxylation, and c) surface amination. The effects of these modifications will be tested in each of the following Specific Aims:
Specific Aim 1. Evaluate the fate of inhaled MWCNT, Specific Aim 2. Demonstrate that aspiration of multiwalled carbon nanotubes alters hemostasis and myocardial response to ischemia and reperfusion.
Specific Aim 3. Test the hypothesis that inhalation of MWCNT alters vascular reactivity via impared adenosine signaling.
Specific Aim 4. Assess the role of endothiela nitric oxide, oxidative stress and vascular function in MWCNT cardiotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016246-04
Application #
7858173
Study Section
Special Emphasis Panel (ZES1-SET-G (NT))
Program Officer
Nadadur, Srikanth
Project Start
2007-09-14
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$338,797
Indirect Cost
Name
East Carolina University
Department
Physiology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Thompson, Leslie C; Holland, Nathan A; Snyder, Ryan J et al. (2016) Pulmonary instillation of MWCNT increases lung permeability, decreases gp130 expression in the lungs, and initiates cardiovascular IL-6 transsignaling. Am J Physiol Lung Cell Mol Physiol 310:L142-54
Holland, N A; Becak, D P; Shannahan, Jonathan H et al. (2015) Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate-capped Nanosilver. J Nanomed Nanotechnol 6:
Vidanapathirana, A K; Thompson, L C; Odom, J et al. (2014) Vascular Tissue Contractility Changes Following Late Gestational Exposure to Multi-Walled Carbon Nanotubes or their Dispersing Vehicle in Sprague Dawley Rats. J Nanomed Nanotechnol 5:
Vidanapathirana, Achini K; Thompson, Leslie C; Mann, Erin E et al. (2014) PVP formulated fullerene (C60) increases Rho-kinase dependent vascular tissue contractility in pregnant Sprague Dawley rats. Reprod Toxicol 49:86-100
Wingard, Christopher J; Holland, Nathan A; Thompson, Leslie C et al. (2014) The need for reflective consideration of an integrative understanding of cardiovascular consequences to PVP formulated C60 exposure. Toxicol Sci 141:327-8
Thompson, Leslie C; Frasier, Chad R; Sloan, Ruben C et al. (2014) Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts. Nanotoxicology 8:38-49
Urankar, Rakhee N; Lust, Robert M; Mann, Erin et al. (2012) Expansion of cardiac ischemia/reperfusion injury after instillation of three forms of multi-walled carbon nanotubes. Part Fibre Toxicol 9:38
Katwa, Pranita; Wang, Xiaojia; Urankar, Rakhee N et al. (2012) A carbon nanotube toxicity paradigm driven by mast cells and the IL-??/ST? axis. Small 8:2904-12
Mann, Erin E; Thompson, Leslie C; Shannahan, Jonathan H et al. (2012) Changes in cardiopulmonary function induced by nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol 4:691-702
Wang, Xiaojia; Katwa, Pranita; Podila, Ramakrishna et al. (2011) Multi-walled carbon nanotube instillation impairs pulmonary function in C57BL/6 mice. Part Fibre Toxicol 8:24

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