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ESR evidence for in vivo formation of free radicals in tissue of mice exposed to single-walled carbon nanotubes.

Shvedova-AA; Kisin-ER; Murray-AR; Mouithys-Mickalad-A; Stadler-K; Mason-RP; Kadiiska-M
Free Radic Biol Med 2014 Aug; 73:154-165
Nanomaterials are being utilized in an increasing variety of manufactured goods. Because of their unique physicochemical, electrical, mechanical, and thermal properties, single-walled carbon nanotubes (SWCNTs) have found numerous applications in the electronics, aerospace, chemical, polymer, and pharmaceutical industries. Previously, we have reported that pharyngeal exposure of C57BL/6 mice to SWCNTs caused dose-dependent formation of granulomatous bronchial interstitial pneumonia, fibrosis, oxidative stress, acute inflammatory/cytokine responses, and a decrease in pulmonary function. In the current study, we used electron spin resonance (ESR) to directly assess whether exposure to respirable SWCNTs caused formation of free radicals in the lungs and in two distant organs, the heart and liver. Here we report that exposure to partially purified SWCNTs (HiPco technique, Carbon Nanotechnologies, Inc., Houston, TX, USA) resulted in the augmentation of oxidative stress as evidenced by ESR detection of a-(4-pyridyl-1-oxide)-N-tert-butylnitrone spin-trapped carbon-centered lipid-derived radicals recorded shortly after the treatment. This was accompanied by a significant depletion of antioxidants and elevated biomarkers of inflammation presented by recruitment of inflammatory cells and an increase in proinflammatory cytokines in the lungs, as well as development of multifocal granulomatous pneumonia, interstitial fibrosis, and suppressed pulmonary function. Moreover, pulmonary exposure to SWCNTs also caused the formation of carbon-centered lipid-derived radicals in the heart and liver at later time points (day 7 postexposure). Additionally, SWCNTs induced a significant accumulation of oxidatively modified proteins, increase in lipid peroxidation products, depletion of antioxidants, and inflammatory response in both the heart and the liver. Furthermore, the iron chelator deferoxamine noticeably reduced lung inflammation and oxidative stress, indicating an important role for metal-catalyzed species in lung injury caused by SWCNTs. Overall, we provide direct evidence that lipid-derived free radicals are a critical contributor to tissue damage induced by SWCNTs not only in the lungs, but also in distant organs.
Nanotechnology; Animals; Laboratory-animals; Tissue-culture; Chemical-properties; Electrical-properties; Mechanical-properties; Thermal-properties; Respiratory-infections; Fibrosis; Oxidative-metabolism; Pulmonary-function; Pulmonary-system; Pulmonary-system-disorders; Respiratory-system-disorders; Lung; Exposure-levels; Risk-factors; Biomarkers
Anna Shvedova, NIOSH, Pathology and Physiology Research Branch, Health Effects Laboratory Division, 1095 Willowdale Road, Morgantown, WV 26505
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Free Radical Biology and Medicine