Oxidized carbon black nanoparticles induce endothelial damage through C-X-C chemokine receptor 3-mediated pathway
Nairrita Majumder,
Murugesan Velayutham,
Dimitrios Bitounis,
Vamsi K. Kodali,
Md Habibul Hasan Mazumder,
Jessica Amedro,
Valery V. Khramtsov,
Aaron Erdely,
Timothy Nurkiewicz,
Philip Demokritou,
Eric E. Kelley,
Salik Hussain
Affiliations
Nairrita Majumder
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA
Murugesan Velayutham
Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA; Department of Biochemistry, West Virginia University, School of Medicine, USA
Dimitrios Bitounis
Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Vamsi K. Kodali
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA; National Institute for Occupational Safety and Health, Morgantown, WV, USA
Md Habibul Hasan Mazumder
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA
Jessica Amedro
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA
Valery V. Khramtsov
Department of Biochemistry, West Virginia University, School of Medicine, USA
Aaron Erdely
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA; National Institute for Occupational Safety and Health, Morgantown, WV, USA
Timothy Nurkiewicz
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA; National Institute for Occupational Safety and Health, Morgantown, WV, USA
Philip Demokritou
Center for Nanotechnology and Nanotoxicology, Department of Environmental Health, T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
Eric E. Kelley
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA
Salik Hussain
Department of Physiology and Pharmacology, West Virginia University, School of Medicine, USA; Center for Inhalation Toxicology (iTOX), West Virginia University, School of Medicine, USA; Corresponding author. 64 Medical Center Drive. Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, 26506-9229, USA.
Oxidation of engineered nanomaterials during application in various industrial sectors can alter their toxicity. Oxidized nanomaterials also have widespread industrial and biomedical applications. In this study, we evaluated the cardiopulmonary hazard posed by these nanomaterials using oxidized carbon black (CB) nanoparticles (CBox) as a model particle.Particle surface chemistry was characterized by X-ray photo electron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FTIR). Colloidal characterization and in vitro dosimetry modeling (particle kinetics, fate and transport modeling) were performed. Lung inflammation was assessed following oropharyngeal aspiration of CB or oxidized CBox particles (20 μg per mouse) in C57BL/6J mice. Toxicity and functional assays were also performed on murine macrophage (RAW 264.7) and endothelial cell lines (C166) with and without pharmacological inhibitors. Oxidant generation was assessed by electron paramagnetic resonance spectroscopy (EPR) and via flow cytometry. Endothelial toxicity was evaluated by quantifying pro-inflammatory mRNA expression, monolayer permeability, and wound closure.XPS and FTIR spectra indicated surface modifications, the appearance of new functionalities, and greater oxidative potential (both acellular and in vitro) of CBox particles. Treatment with CBox demonstrated greater in vivo inflammatory potentials (lavage neutrophil counts, secreted cytokine, and lung tissue mRNA expression) and air-blood barrier disruption (lavage proteins). Oxidant-dependent pro-inflammatory signaling in macrophages led to the production of CXCR3 ligands (CXCL9,10,11). Conditioned medium from CBox-treated macrophages induced significant elevation in endothelial cell pro-inflammatory mRNA expression, enhanced monolayer permeability and impairment of scratch healing in CXCR3 dependent manner.In summary, this study mechanistically demonstrated an increased biological potency of CBox particles and established the role of macrophage-released chemical mediators in endothelial damage.
