Engineered nanomaterials, including carbon nanotubes (CNT), have unique physicochemical properties with potential to impact diverse aspects of society. While there are currently over 800 products on the market that contain nanomaterials, there is a significant lack of toxicity testing associated with these products despite emerging observations of adverse respiratory and cardiovascular effects associated with nanomaterials. In addition, due to their unique properties, nanomaterials have the potential to interact with biological systems in a distinctive manner. However, to date there is only a limited understanding of how nanomaterials interact with biological systems;and therefore we lack the ability to predict which nanomaterials are safe and which are toxic;and how nanomaterials might be engineered to avoid toxic side effects. Inhalation of single-walled CNT (SWCNT) or multi-walled CNT (MWCNT) has been reported to cause lung inflammation and fibrosis. In addition, recent work in our laboratory suggests that exposure to MWCNT impacts the cardiovascular system. Mast cells may well be critical effector cells in inducing these toxic effects. We have preliminary, but convincing evidence that CNT pulmonary exposure activates resident mast cells, either directly or indirectly, thereby contributing to both pulmonary and cardiovascular pathology. Our preliminary findings support the hypothesis that CNT exposure activates mast cells through an IL-33 dependent mechanism which results in pulmonary inflammation and adverse cardiovascular events due to the resultant release of inflammatory mediators, including osteopontin (OPN). We will test this hypothesis by: 1) examining mast cell activation in lungs of mice exposed to MWCNTs;2) examining the role of IL-33 in mediating mast cell activation;3) elucidating the role of mast cells in contributing to altered vascular reactivity within the cardiovascular system;4) using cell based models to establish the mechanisms by which MWCNTs lead to mast cell activation. This proposal is novel in that it identifies an unrecognized, yet significant mechanism by which CNTs lead to toxicity. Understanding this mechanism will allow us to design better models and in vitro screening tools to predict nanomaterial toxicity. Lastly, this proposal provides an important translational application in that by elucidating the proposed mechanism, we will provide support for the use of mast cell directed strategies, such as cromolyn sodium, to intervene early after exposure to prevent subsequent inflammation and fibrosis.

Public Health Relevance

The use of engineered nanomaterials in the biotechnology industry and manufacturing setting has increased dramatically in recent years. Yet, the properties that make nanoparticles useful in science and medicine also present potential safety concerns. This proposal will elucidate a mechanism, involving mast cell activation, by which multi-walled carbon nanotubes elicit pulmonary and cardiovascular toxicities. Completion of this proposal will provide the data needed to assess the toxicity associated with additional nanomaterials and will provide important translational implications as the data will begin to support the notion that early intervention with mast cell directed medicines following nanotube exposure may provide beneficial therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES019311-02S1
Application #
8332610
Study Section
Special Emphasis Panel (ZES1-TN-J (R))
Program Officer
Nadadur, Srikanth
Project Start
2010-08-10
Project End
2015-03-31
Budget Start
2011-12-01
Budget End
2012-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$79,596
Indirect Cost
$15,924
Name
East Carolina University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Raghavendra, Achyut J; Gregory, Wren E; Slonecki, Tyler J et al. (2018) Three-photon imaging using defect-induced photoluminescence in biocompatible ZnO nanoparticles. Int J Nanomedicine 13:4283-4290
Persaud, Indushekhar; Shannahan, Jonathan H; Raghavendra, Achyut J et al. (2018) Biocorona formation contributes to silver nanoparticle induced endoplasmic reticulum stress. Ecotoxicol Environ Saf 170:77-86
Alsaleh, Nasser B; Brown, Jared M (2018) Immune responses to engineered nanomaterials: current understanding and challenges. Curr Opin Toxicol 10:8-14
Drew, Nathan M; Kuempel, Eileen D; Pei, Ying et al. (2017) A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: Proof of concept evaluation. Regul Toxicol Pharmacol 89:253-267
Johnson, Monica M; Mendoza, Ryan; Raghavendra, Achyut J et al. (2017) Contribution of engineered nanomaterials physicochemical properties to mast cell degranulation. Sci Rep 7:43570
Bai, Wei; Wu, Zheqiong; Mitra, Somenath et al. (2016) Effects of multiwalled carbon nanotube surface modification and purification on bovine serum albumin binding and biological responses. J Nanomater 2016:
Shannahan, Jonathan H; Fritz, Kristofer S; Raghavendra, Achyut J et al. (2016) From the Cover: Disease-Induced Disparities in Formation of the Nanoparticle-Biocorona and the Toxicological Consequences. Toxicol Sci 152:406-16
Alsaleh, Nasser B; Persaud, Indushekhar; Brown, Jared M (2016) Silver Nanoparticle-Directed Mast Cell Degranulation Is Mediated through Calcium and PI3K Signaling Independent of the High Affinity IgE Receptor. PLoS One 11:e0167366
Aldossari, Abdullah A; Shannahan, Jonathan H; Podila, Ramakrishna et al. (2015) Influence of physicochemical properties of silver nanoparticles on mast cell activation and degranulation. Toxicol In Vitro 29:195-203
Shannahan, Jonathan H; Podila, Ramakrishna; Aldossari, Abdullah A et al. (2015) Formation of a protein corona on silver nanoparticles mediates cellular toxicity via scavenger receptors. Toxicol Sci 143:136-46

Showing the most recent 10 out of 33 publications