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Mechanistic links between the lung and the systemic microcirculation after nanoparticle exposure.

Nurkiewicz-TR; Donlin-M; Hubbs-A; Goodwill-A; Frisbee-J; Chen-B; Frazer-D; Castranova-V
Toxicologist 2009 Mar; 108(1):279
Previous studies in our laboratory have shown that pulmonary nanoparticle exposure causes peripheral microvascular dysfunction. This dysfunction is characterized by impaired endothelium-dependent arteriolar dilation and venular leukocyte adhesion. The mechanisms that produce these effects remain poorly understood. The purpose of this study was to determine if neurological mechanisms and/or circulating leukocytes play a fundamental role between pulmonary exposure and peripheral microvascular dysfunction. Rats were exposed to TiO2 nanoparticles via inhalation (primary particle diameter approximately 21 nm) at depositions of 4-90 ug/rat. Some rats received a bolus dose of cyclophosphamide (200 ug/g, i.p.) 3 days prior to nanoparticle exposure to deplete circulating neutrophils. The spinotrapezius muscle was prepared for intravital microscopy 24 hrs after exposures. Intraluminal infusion of the Ca2+ ionophore A23187 (10-7 M, pipette concentration) was used to evaluate endothelium- dependent arteriolar dilation. Histological sections of the spinotrapezius muscle and lung were prepared, and plasma was sampled from each rat for multiplex analyses. Following nanoparticle exposure, plasma IL-1, 2, 13 and ICAM-1 were altered. Consistent with previous experiments, nanoparticle exposure significantly limited arteriolar dilation (in response to A23187) to 0-7% of the normal maximum response. Co-incubation with the fast Na+ channel antagonist tetrodotoxin (TTX, 10-6 M) restored dilation by as much as 54%. Neutrophil depletion similarly resored dilation by as much as 42%. These mechanistic data support prominent hypotheses that suggest peripheral vascular effects associated with particle exposure are due to neurogenic and/or inflammatory mechanisms.
Biological-effects; Biological-factors; Blood-vessels; Blood-analysis; Blood-plasma; Dose-response; Exposure-assessment; Exposure-levels; Exposure-methods; Inhalation-studies; Laboratory-animals; Lung-disorders; Lung-function; Lung-irritants; Microscopic-analysis; Microscopy; Musculoskeletal-system; Particulates; Pulmonary-system-disorders; Pulmonary-disorders; Pulmonary-function-tests; Particle-aerodynamics; Particulate-dust; Respiratory-hypersensitivity; Respiratory-irritants; Respiratory-system-disorders; Statistical-analysis; Nanotechnology
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The Toxicologist. Society of Toxicology 48th Annual Meeting and ToxExpo, March 15-19, 2009, Baltimore, Maryland