Pulmonary nanoparticle exposure disrupts systemic microvascular nitric oxide signaling.
Nurkiewicz-TR; Porter-W; Hubbs-AF; Stone-S; Chen-BT; Frazer-DG; Boegehold-MA; Castranova-V
Toxicol Sci 2009 Jul; 110(1):191-203
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 similar to 1 mu m) and TiO2 nanoparticles (primary particle diameter similar to 21 nm) via aerosol inhalation at depositions of 4-90 mu g 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. 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 similar to 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.
Animals; Animal-studies; Biochemical-analysis; Biological-effects; Biological-monitoring; Biological-systems; Biological-transport; Blood-vessels; Chemical-analysis; Chemical-hypersensitivity; Chemical-properties; Chemical-reactions; Chemical-structure; Chemical-synthesis; Dose-response; Exposure-assessment; Exposure-levels; Exposure-limits; Exposure-methods; Inhalation-studies; Laboratory-animals; Laboratory-testing; Microbiology; Microchemistry; Microscopic-analysis; Microscopy; Oxidative-processes; Particle-aerodynamics; Particulates; Particulate-sampling-methods; Pulmonary-system; Respiratory-hypersensitivity; Respiratory-irritants; Nanotechnology;
Author Keywords: systemic microcirculation; nitric oxide; nanoparticle; inhalation; arteriole; endothelium
Timothy R. Nurkiewicz, Center for Cardiovascular and Respiratory Sciences, 1 Medical Center Drive, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9105