Biomedical Sciences ETDs

Author

Mario Aragon

Publication Date

5-1-2016

Abstract

Assessing the mechanisms underlying adverse cardiovascular effects induced by inhaled toxins presents a substantial research challenge. We propose that blood carries an as yet unknown "inflammatory potential" consisting of modified proteins or other biomolecules and reaction byproducts that affects a pathological bioactivity which can be assessed using naïve endothelial cells and blood vessels. The approach involves applying serum from exposed animals to cultured primary endothelial cells or ex vivo isolated arteries. Mice were exposed to multi-walled carbon nanotubes (MWCNT; 0, 10 or 40 μg) or other pollutants via pharyngeal aspiration and serum was collected at 4 and 24 h post-exposure. Serum from exposed mice increased endothelial cell surface vascular cell adhesion molecule-1 (VCAM-1) and intracellular adhesion molecule-1 (ICAM-1) expression and proinflammatory transcripts, and decreased ATP-stimulated nitric oxide (NO) production. The functional impact of this loss of NO bioavailability was confirmed via myography, in which serum from pollutant-exposed mice significantly impaired vasodilation to acetylcholine. In addition, serum from pollutant-exposed mice reduced cell migration in a traditional scratch assay experiment. In vivo MWCNT exposure was able to both increase the permeability of the Blood Brain Barrier (BBB), as well as induce transcription of pro- inflammatory cytokines in the hippocampus and frontal cortex regions of the brain. This affect was abolished with the treatment of fasudil, or the absence of CD36. There was also evidence of astrocyte activation in the short and microglia activation at 24 hours. CD 36 has also been identified as playing a key role in mediating loss of vasodilatory properties ex vivo. In conclusion, pulmonary exposure to MWCNT dynamically alters circulating factors, which promotes endothelial cell activation, decreased NO bioavailability, and altered functionality all directionally predicting adverse cardiovascular outcomes.

Keywords

Multiwalled Carbon Nanotubes, inflammation, Blood Brain Barrier, Cardiovascular, lungs, inhalation

Sponsors

NIH

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Advisor

Campen, Matthew

First Committee Member (Chair)

Burchiel, Scott

Second Committee Member

Walker, Mary

Third Committee Member

Kanagy, Nancy

Fourth Committee Member

Erdely, Aaron

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