Department of Pharmaceutical Sciences, West Virginia University, 1, Medical Center Drive, Morgantown, WV 26506, USA.
Department of Chemical Engineering, Statler College of Engineering and Mineral Resources, West Virginia University, 395 Evansdale Drive, PO Box 6102, Morgantown, WV 26506, USA.
Int J Mol Sci. 2014 Apr 29;15(5):7444-61. doi: 10.3390/ijms15057444.
Given their extremely small size and light weight, carbon nanotubes (CNTs) can be readily inhaled by human lungs resulting in increased rates of pulmonary disorders, particularly fibrosis. Although the fibrogenic potential of CNTs is well established, there is a lack of consensus regarding the contribution of physicochemical attributes of CNTs on the underlying fibrotic outcome. We designed an experimentally validated in vitro fibroblast culture model aimed at investigating the effect of fiber length on single-walled CNT (SWCNT)-induced pulmonary fibrosis. The fibrogenic response to short and long SWCNTs was assessed via oxidative stress generation, collagen expression and transforming growth factor-beta (TGF-β) production as potential fibrosis biomarkers. Long SWCNTs were significantly more potent than short SWCNTs in terms of reactive oxygen species (ROS) response, collagen production and TGF-β release. Furthermore, our finding on the length-dependent in vitro fibrogenic response was validated by the in vivo lung fibrosis outcome, thus supporting the predictive value of the in vitro model. Our results also demonstrated the key role of ROS in SWCNT-induced collagen expression and TGF-β activation, indicating the potential mechanisms of length-dependent SWCNT-induced fibrosis. Together, our study provides new evidence for the role of fiber length in SWCNT-induced lung fibrosis and offers a rapid cell-based assay for fibrogenicity testing of nanomaterials with the ability to predict pulmonary fibrogenic response in vivo.
由于其极其微小的尺寸和轻重量，碳纳米管（CNTs）很容易被人体肺部吸入，导致肺部疾病发生率增加，特别是纤维化。尽管 CNTs 的纤维生成潜力已得到充分证实，但对于 CNTs 的物理化学特性对潜在纤维化结果的贡献，仍缺乏共识。我们设计了一种经过实验验证的体外成纤维细胞培养模型，旨在研究纤维长度对单壁 CNT（SWCNT）诱导的肺纤维化的影响。通过氧化应激产生、胶原蛋白表达和转化生长因子-β（TGF-β）产生来评估短纤维和长纤维 SWCNT 的致纤维化反应，作为潜在的纤维化生物标志物。长 SWCNT 在活性氧（ROS）反应、胶原蛋白产生和 TGF-β释放方面明显比短 SWCNT 更有效。此外，我们在体外模型中验证了长度依赖性体外致纤维化反应的发现，从而支持了该体外模型的预测价值。我们的结果还表明，ROS 在 SWCNT 诱导的胶原蛋白表达和 TGF-β激活中起关键作用，表明了长度依赖性 SWCNT 诱导纤维化的潜在机制。总之，本研究为纤维长度在 SWCNT 诱导的肺纤维化中的作用提供了新的证据，并提供了一种快速的基于细胞的纳米材料致纤维化测试方法，具有预测体内肺纤维化反应的能力。
