Abstract
Pulmonary exposure to inhaled particulates elicits complex inflammatory and fibrotic responses that may progress to chronic fibrosis. The fibrogenic potentials of respirable particulates are influenced by their physicochemical properties and their interactions with major pathways to drive fibrotic development in the lung. Macrophages were exposed to six carbon nanotubes (CNTs) of varying dimensions, crystalline silica, or carbon black (CB), with lipopolysaccharide (LPS) and transforming growth factor (TGF)-β1 as positive controls. Macrophage-conditioned media was collected and applied to cultures of human pulmonary fibroblast line WI38-VA13 to induce myofibroblast transformation. Multi-walled and single-walled CNTs (MWCNTs and SWCNTs, respectively) and silica, but not CB, stimulated robust myofibroblast transformation through macrophage-conditioned media. On an equal weight basis, MWCNTs induced higher induction than SWCNTs. High induction was observed for MWCNTs with a long and slender or a short and rigid shape, and silica, at levels comparable to those by LPS and TGF-β1. Fibrogenic particulates induced high levels of IL-1β mRNA expression and protein secretion that are required for macrophage-guided myofibroblast transformation. Induction of IL-1β is dependent on the activation of the NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome and ROS (reactive oxygen species) production in macrophages, as inhibition of NLRP3 by MCC950 and reduction of ROS production by N-acetylcysteine blocked NLRP3 activation, IL-1β induction, and fibroblast activation and differentiation. Therefore, fibrogenic CNTs and silica, but not CB, elicit robust macrophage-guided myofibroblast transformation, which depends on the induction of IL-1β through the NLRP3 inflammasome pathway and the increased production of ROS in macrophages.
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This work was funded to Q.M. by the Health Effects Laboratory Division and the Nanotechnology Research Center at National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, USA, No. 8939050W.
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Hindman, B., Ma, Q. Carbon nanotubes and crystalline silica stimulate robust ROS production, inflammasome activation, and IL-1β secretion in macrophages to induce myofibroblast transformation. Arch Toxicol 93, 887–907 (2019). https://doi.org/10.1007/s00204-019-02411-y
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DOI: https://doi.org/10.1007/s00204-019-02411-y