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, USA.
Arch Toxicol. 2018 Nov;92(11):3291-3305. doi: 10.1007/s00204-018-2306-9. Epub 2018 Sep 18.
Pulmonary fibrosis is a poorly understood pathologic condition. Carbon nanotubes (CNTs) are nanomaterials with potentials for broad applications. CNTs can induce pulmonary fibrosis in animals, a cause for concern for exposed workers and consumers. Given the large number of CNTs available on the market and the seemingly infinite number of ways these particles can be modified in ways that may affect toxicity, in vitro models that can be used to quickly and effectively investigate the relative fibrogenicity of CNTs are much needed. Here we analyzed the fibrogenic potentials of six CNTs of varying physical properties and crystalline silica using two- and three-dimensional (2D and 3D, respectively) in vitro models. WI38-VA13 human pulmonary fibroblasts were treated with CNTs or silica, with TGF-β1, a known inducer of fibroblast differentiation, as positive control. The cells were examined for fibrotic matrix alterations, including myofibroblast transformation, matrix remodeling, and matrix contraction. While all tested CNTs induced myofibroblast differentiation in 2D and 3D cultures, the 3D culture allowed the examination of myofibroblast clustering, collagen deposition and rearrangement, cell division, and matrix contraction in response to fibrogenic exposures, processes critical for fibrosis in vivo. At 1 µg/ml, MWCNTs elicit higher induction of myofibroblast differentiation and matrix remodeling than SWCNTs. Among MWCNTs, those with the highest and lowest aspect ratios produced the largest effects, which were comparable to those by TGF-β1 and higher than those by silica. Thus, the 3D collagen-based model enables the study of matrix fibrotic processes induced by CNTs and silica particles directly and effectively.
肺纤维化是一种了解甚少的病理状况。碳纳米管（CNTs）是具有广泛应用潜力的纳米材料。CNTs 可在动物中引起肺纤维化，这引起了暴露于其中的工人和消费者的关注。鉴于市场上存在大量的 CNT，并且这些颗粒似乎可以通过改变其性质的方式进行无限修改，从而可能影响其毒性，因此非常需要能够快速有效地研究 CNT 相对纤维形成能力的体外模型。在这里，我们使用二维（2D）和三维（3D）体外模型分析了六种具有不同物理性质和结晶二氧化硅的 CNT 的纤维形成潜力。用 CNT 或二氧化硅处理 WI38-VA13 人肺成纤维细胞，用 TGF-β1（已知的成纤维细胞分化诱导剂）作为阳性对照。检查细胞的纤维基质改变，包括肌成纤维细胞转化、基质重塑和基质收缩。虽然所有测试的 CNT 都在 2D 和 3D 培养物中诱导了肌成纤维细胞分化，但 3D 培养物允许检查肌成纤维细胞聚集、胶原蛋白沉积和重排、细胞分裂以及对纤维发生暴露的基质收缩，这些过程对于体内纤维化至关重要。在 1μg/ml 时，MWCNTs 比 SWCNTs 更能诱导肌成纤维细胞分化和基质重塑。在 MWCNTs 中，具有最高和最低纵横比的那些产生的效果最大，与 TGF-β1 的效果相当，高于二氧化硅的效果。因此，基于 3D 胶原的模型能够直接有效地研究 CNT 和二氧化硅颗粒诱导的基质纤维化过程。
