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Nanoparticles alter cyclooxygenase activity in microvascular dysfunction.

Authors
Knuckles-TL; Yi-J; Frazer-D; Cumpston-J; Chen-B; Castranova-V; Nurkiewicz-TR
Source
Toxicologist 2011 Mar; 120(Suppl 2):316
NIOSHTIC No.
20038591
Abstract
The widespread increase in the production and use of nanomaterials has increased the potential for nanoparticle exposure; however, little is known about the biologic effects of nanoparticle inhalation. We have shown that blunted nitric oxide (NO) production significantly contributes to nanoparticle induced microvascular dysfunction. However, it cannot account for all of the microvascular effects of nanoparticle exposure. The purpose of this study was to evaluate alternative mechanisms of microvascular dysfunction. Rats were exposed to nano-TiO2 (primary particle size approximately 21 nm) aerosols in our Inhalation Facility at a concentration of 4-5 mg/m3 with a count median aerodynamic diameter of approximately 145 nm for 4-6 hours yielding a total calculated lung burden of 30 microg. 24 h post-exposure, the spinotrapezius muscle was prepared for intravital microscopy. We assessed arteriolar function via perivascular nerve stimulation and active hyperemia with or without inhibitors for endogenous NO production or cyclooxygenase (COX) products. NO inhibition increased vasoconstriction and decreased vasodilation in control but not in exposed animals. COX inhibition had no effect on vasoconstriction in either group but overtly blunted vasodilation in exposed animals. Based on these results, we then determined if exposure altered sensitivity to COX products. Suffusion of the muscle with U46619 (1-100 nM), a thromboxane A2 mimetic, led to a significantly greater vasoconstriction in exposed animals compared to control (max % of control -22 +/- 3.4% sham, -31 +/- 4.0% exposed). Furthermore, suffusion of iloprost (2.8-28 nM), a prostacyclin mimetic, led to a slight increase in vasodilation in the exposed animals compared to control (max % of control 177 +/- 25% sham, 214 +/- 41% exposed). Hence, the compensatory mechanism for the NO deficit appears to be COX mediated, through enhanced sensitivity and possibly increased endogenous production.
Keywords
Aerosol-particles; Airborne-particles; Biohazards; Biological-effects; Cardiopulmonary-system; Cardiopulmonary-system-disorders; Cardiovascular-disease; Cardiovascular-system; Cardiovascular-system-disorders; Cellular-reactions; Inhalation-studies; Laboratory-animals; Lung-disorders; Lung-irritants; Nanotechnology; Particulates; Physiological-effects; Pulmonary-disorders; Pulmonary-system-disorders; Quantitative-analysis; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Statistical-analysis; Vasoactive-agents
CAS No.
10102-43-9
Publication Date
20110301
Document Type
Abstract
Fiscal Year
2011
NTIS Accession No.
NTIS Price
ISSN
1096-6080
NIOSH Division
HELD
Priority Area
Construction; Manufacturing
Source Name
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC
State
WV; DC
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