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ToxSci Advance Access originally published online on March 6, 2009
Toxicological Sciences 2009 110(1):191-203; doi:10.1093/toxsci/kfp051
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling

Timothy R. Nurkiewicz*,{dagger},{ddagger},1, Dale W. Porter{dagger},§, Ann F. Hubbs§, Samuel Stone§, Bean T. Chen§, David G. Frazer{dagger},§, Matthew A. Boegehold*,{dagger} and Vincent Castranova§

* Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, West Virginia 26506 {dagger} Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, West Virginia 26506 {ddagger} Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, West Virginia 26506 § Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26506

1 To whom correspondence should be addressed at Center for Cardiovascular and Respiratory Sciences, 1 Medical Center Drive, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9105. Fax: (304) 293-5513. E-mail: tnurkiewicz{at}hsc.wvu.edu.

Received January 19, 2009; accepted March 2, 2009


  Abstract

We have shown that pulmonary nanoparticle exposure impairs endothelium dependent dilation in systemic arterioles. However, the mechanism(s) through which this effect occurs is/are unclear. The purpose of this study was to identify alterations in the production of reactive species and endogenous nitric oxide (NO) after nanoparticle exposure, and determine the relative contribution of hemoproteins and oxidative enzymes in this process. Sprague-Dawley rats were exposed to fine TiO2 (primary particle diameter ~1 µm) and TiO2 nanoparticles (primary particle diameter ~21 nm) via aerosol inhalation at depositions of 4–90 µg per rat. As in previous intravital experiments in the spinotrapezius muscle, dose-dependent arteriolar dilations were produced by intraluminal infusions of the calcium ionophore A23187. [GenBank] Nanoparticle exposure robustly attenuated these endothelium-dependent responses. However, this attenuation was not due to altered microvascular smooth muscle NO sensitivity because nanoparticle exposure did not alter arteriolar dilations in response to local sodium nitroprusside iontophoresis. Nanoparticle exposure significantly increased microvascular oxidative stress by ~60%, and also elevated nitrosative stress fourfold. These reactive stresses coincided with a decreased NO production in a particle deposition dose-dependent manner. Radical scavenging, or inhibition of either myeloperoxidase or nicotinamide adenine dinucleotide phosphate oxidase (reduced) oxidase partially restored NO production as well as normal microvascular function. These results indicate that in conjunction with microvascular dysfunction, nanoparticle exposure also decreases NO bioavailability through at least two functionally distinct mechanisms that may mutually increase local reactive species.

Key Words: systemic microcirculation; nitric oxide; nanoparticle; inhalation; arteriole; endothelium.


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