Nanoparticle inhalation increases microvascular oxidative stress and compromises nitric oxide bioavailability.
Nurkiewicz-TR; Hubbs-A; Mosely-A; Chen-B; Frazer-D; Boegehold-M; Dreher-K; Castranova-V
Toxicologist 2009 Mar; 108(1):279
We have shown that pulmonary nanoparticle exposure impairs endothelium dependent dilation in systemic arterioles. However, the mechanism(s) through which this effect occurs are unclear. The purpose of this study was to identify alterations in the production of oxidative stress and endogenous nitric oxide (NO) after nanoparticle exposure, and determine the relative contribution of hemoproteins and oxidative enzymes in this process. Rats were exposed to TiO2 nanoparticles via inhalation (primary particle diameter ~21 nm) at depositions of 4-90 mu g/rat. The spinotrapezius muscle was prepared for intravital microscopy 24 hrs after exposures. Intraluminal infusion of the Ca2+ ionophore A23187 was used to evaluate endothelium- dependent arteriolar dilation. Endogenous microvascular NO production was measured with an electrochemical sensor. Oxidative stress in the microvascular wall was quantified via dihydroethidium fluorescence (O2 - probe). Histological sections of pulmonary tissue revealed nanoparticle uptake by alveolar macrophages, and migration to nearby lymph tissue. TiO2 nanoparticles quenched spontaneous NO signals generated in vitro by S-Nitroso-N-acetyl-D,L-penicillamine (550 mM). As in previous experiments, A23187 produced dose-dependent arteriolar dilations (10- 69% of maximum response). Nanoparticle exposure robustly attenuated this to 6- 16% of the maximum response. Nanoparticle exposure also increased microvascular oxidative stress by ~60%, and decreased NO production. Inhibition of either myeloperoxidase (4-aminobenzoic hydrazide, 10 um) or NADPH oxidase (apocynin, 10-4 M) partially restored NO production and normal microvascular function. These results indicate that in conjunction with microvascular dysfunction, nanoparticle exposure also increases local oxidative stress and decreases NO bioavailability.
Biological-effects; Biological-factors; Blood-vessels; Cardiovascular-function; Cardiovascular-system; Cardiovascular-system-disorders; Dose-response; Exposure-assessment; Exposure-levels; Exposure-methods; Electrochemical-analysis; Electrochemical-reactions; Electrochemistry; Inhalation-studies; Laboratory-animals; Microscopic-analysis; Microscopy; Musculoskeletal-system; Oxidative-enzymes; Oxidative-metabolism; Particulates; Pulmonary-system-disorders; Statistical-analysis; Nanotechnology
The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland