ToxSci Advance Access published online on March 6, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp051
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Pulmonary Nanoparticle Exposure Disrupts Systemic Microvascular Nitric Oxide Signaling
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* Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, WV, USA
Department of Physiology and Pharmacology, West Virginia University School of Medicine, Morgantown, WV, USA
Department of Neurobiology and Anatomy, West Virginia University School of Medicine, Morgantown, WV, USA
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, USA
Address For Correspondence: Timothy R. Nurkiewicz, Ph.D., Center for Cardiovascular and Respiratory Sciences, 1 Medical Center Drive, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, 26506-9105, office: (304) 293-7328, fax: (304) 293-5513, tnurkiewicz{at}hsc.wvu.edu
Received January 19, 2009; revision received February 24, 2009; accepted March 2, 2009
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Abstract |
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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/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 four-fold. These reactive stresses coincided with a decreased NO production in a particle deposition dose-dependent manner. Radical scavenging, or inhibition of either myeloperoxidase (MPO) or NADPH 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.
Dale W. Porter - dhp7{at}cdc.gov, Ann F. Hubbs – afh0{at}cdc.gov, Samuel Stone - zhf9{at}cdc.gov, Bean T. Chen - bdc4{at}cdc.gov, David G. Frazer - dgf1{at}cdc.gov, Matthew A. Boegehold – mboegehold{at}hsc.wvu.edu, Vincent Castranova – vic1{at}cdc.gov