Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, 26505, USA.
Arch Toxicol. 2019 Apr;93(4):887-907. doi: 10.1007/s00204-019-02411-y. Epub 2019 Mar 7.
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.
吸入性颗粒物暴露会引发复杂的炎症和纤维化反应，这些反应可能进展为慢性纤维化。可吸入颗粒物的致纤维化潜力受其物理化学性质及其与主要途径的相互作用影响，这些作用驱动肺部纤维化的发展。用六种不同尺寸的碳纳米管（CNT）、二氧化硅或炭黑（CB）、脂多糖（LPS）和转化生长因子（TGF）-β1 处理巨噬细胞作为阳性对照。收集巨噬细胞条件培养基并应用于人肺成纤维细胞系 WI38-VA13 的培养物中，以诱导肌成纤维细胞转化。多壁和单壁 CNT（MWCNT 和 SWCNT）和二氧化硅，但不是 CB，通过巨噬细胞条件培养基刺激了强大的肌成纤维细胞转化。在同等重量的基础上，MWCNT 诱导的诱导作用高于 SWCNT。长而细或短而硬的 MWCNT 和二氧化硅的诱导作用较高，与 LPS 和 TGF-β1 相当。致纤维化颗粒诱导高水平的白细胞介素 1β（IL-1β）mRNA 表达和蛋白分泌，这些物质是巨噬细胞指导肌成纤维细胞转化所必需的。IL-1β 的诱导依赖于巨噬细胞中 NLRP3（NOD 样受体家族，含 pyrin 结构域 3）炎性体和 ROS（活性氧）的产生，MCC950 抑制 NLRP3 和 N-乙酰半胱氨酸减少 ROS 产生可阻断 NLRP3 激活、IL-1β 诱导、成纤维细胞激活和分化。因此，致纤维化的 CNT 和二氧化硅，但不是 CB，引发了强大的巨噬细胞指导的肌成纤维细胞转化，这依赖于 NLRP3 炎性体途径诱导的 IL-1β 增加和巨噬细胞中 ROS 的产生增加。
