Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
Netherlands Organization for Applied Scientific Research, TNO, Zeist, The Netherlands.
Toxicol In Vitro. 2018 Mar;47:137-146. doi: 10.1016/j.tiv.2017.11.005. Epub 2017 Nov 15.
The epithelium that covers the conducting airways and alveoli is a primary target for inhaled toxic substances, and therefore a focus in inhalation toxicology. The increasing concern about the use of animal models has stimulated the development of in vitro cell culture models for analysis of the biological effects of inhaled toxicants. However, the validity of the current in vitro models and their acceptance by regulatory authorities as an alternative to animal models is a reason for concern, and requires a critical review. In this review, focused on human lung epithelial cell cultures as a model for inhalation toxicology, we discuss the choice of cells for these models, the cell culture system used, the method of exposure as well as the various read-outs to assess the cellular response. We argue that rapid developments in the 3D culture of primary epithelial cells, the use of induced pluripotent stem cells for generation of lung epithelial cells and the development of organ-on-a-chip technology are among the important developments that will allow significant advances in this field. Furthermore, we discuss the various routes of application of inhaled toxicants by air-liquid interface models as well as the vast array of read-outs that may provide essential information. We conclude that close collaboration between researchers from various disciplines is essential for development of valid methods that are suitable for replacement of animal studies for inhalation toxicology.
覆盖传导气道和肺泡的上皮组织是吸入性毒性物质的主要靶标，因此也是吸入毒理学的重点。人们对动物模型使用的关注日益增加，刺激了用于分析吸入性毒性物质的生物效应的体外细胞培养模型的发展。然而，当前体外模型的有效性及其被监管机构作为动物模型替代物的可接受性是令人关注的原因，需要进行批判性审查。在这篇重点关注人肺上皮细胞培养作为吸入毒理学模型的综述中，我们讨论了这些模型中细胞的选择、所使用的细胞培养系统、暴露方法以及用于评估细胞反应的各种检测方法。我们认为，原代上皮细胞的 3D 培养、诱导多能干细胞生成肺上皮细胞的应用以及器官芯片技术的发展是该领域取得重大进展的重要因素。此外，我们还讨论了空气-液体界面模型中吸入性毒性物质的各种应用途径以及可能提供重要信息的大量检测方法。我们得出结论，来自不同学科的研究人员之间的密切合作对于开发适合替代动物研究的吸入毒理学的有效方法是至关重要的。
