title: Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury.
abstract: Commercialization of multiwalled carbon nanotubes (MWCNT)-based applications has been hampered by concerns regarding their lung toxicity potential. Hyaluronic acid (HA) is a ubiquitously found polysaccharide, which is anti-inflammatory in its native high molecular weight form. HA-functionalized smart MWCNTs have shown promise as tumor-targeting drug delivery agents and can enhance bone repair and regeneration. However, it is unclear whether HA functionalization could reduce the pulmonary toxicity potential of MWCNTs. Using in vivo and in vitro approaches, we investigated the effectiveness of MWCNT functionalization with HA in increasing nanotube biocompatibility and reducing lung inflammatory and fibrotic effects. We utilized three-dimensional cultures of differentiated primary human bronchial epithelia to translate findings from rodent assays to humans. We found that HA functionalization increased stability and dispersion of MWCNTs and reduced postexposure lung inflammation, fibrosis, and mucus cell metaplasia compared with nonfunctionalized MWCNTs. Cocultures of fully differentiated bronchial epithelial cells (cultivated at air-liquid interface) and human lung fibroblasts (submerged) displayed significant reduction in injury, oxidative stress, as well as pro-inflammatory gene and protein expression after exposure to HA-functionalized MWCNTs compared with MWCNTs alone. In contrast, neither type of nanotubes stimulated cytokine production in primary human alveolar macrophages. In aggregate, our results demonstrate the effectiveness of HA functionalization as a safer design approach to eliminate MWCNT-induced lung injury and suggest that HA functionalization works by reducing MWCNT-induced epithelial injury.
authors.affiliation: Clinical Research Unit, National Institute of Environmental Health Sciences (NIEHS)/National Institute of Health (NIH) , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Salik
authors.initials: S
authors.lastname: Hussain
authors.affiliation: UC Center for Environmental Implications of Nanotechnology, University of California , Los Angeles, California 90095, United States.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.affiliation: Toxicology Program, Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina 27695, United States.
authors.forename: Alexia J
authors.initials: AJ
authors.lastname: Taylor
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: Clinical Research Unit, National Institute of Environmental Health Sciences (NIEHS)/National Institute of Health (NIH) , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Margaret
authors.initials: M
authors.lastname: George
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Tucker
authors.affiliation: UC Center for Environmental Implications of Nanotechnology, University of California , Los Angeles, California 90095, United States.
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.affiliation: UC Center for Environmental Implications of Nanotechnology, University of California , Los Angeles, California 90095, United States.|School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University , Suzhou 215123, China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Li
authors.affiliation: Toxicology Program, Department of Biological Sciences, North Carolina State University , Raleigh, North Carolina 27695, United States.
authors.forename: James C
authors.initials: JC
authors.lastname: Bonner
authors.affiliation: Clinical Research Unit, National Institute of Environmental Health Sciences (NIEHS)/National Institute of Health (NIH) , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
mesh_terms: D005347:Fibroblasts; D006801:Humans; D006820:Hyaluronic Acid; D008168:Lung; D055370:Lung Injury / Q000517:prevention & control*; D016676:Macrophages, Alveolar; D008970:Molecular Weight; D037742:Nanotubes, Carbon
chemical_list: D037742:Nanotubes, Carbon; D006820:Hyaluronic Acid
keywords: differentiated human bronchial epithelia; fibrosis; hyaluronan; inflammation; lung; mucous metaplasia; multiwalled carbon nanotubes