Using an in vitro human small airway epithelium model, we assessed the biological impact of an aerosol from a candidate modified-risk tobacco product, the tobacco heating system (THS) 2.2, to investigate the potential reduced risk of THS2.2 aerosol exposure compared with cigarette smoke. Following the recommendations of the Institute of Medicine and the Tobacco Product Assessment Consortium, in which modified-risk tobacco products assessment should be performed in comparison with standard conventional products, the effects of the THS2.2 aerosol exposure on the small airway cultures were compared with those of 3R4F cigarette smoke. We used a systems toxicology approach whereby elucidation of toxic effects is derived not only from functional assay readouts but also from omics technologies. Cytotoxicity, ciliary beating function, secretion of pro-inflammatory mediators and histological assessment represented functional assays. The omics data included transcriptomic and miRNA profiles. Exposure-induced perturbations of causal biological networks were computed from the transcriptomic data. The results showed that THS2.2 aerosol exposure at the tested doses elicited lower cytotoxicity levels and lower changes in the secreted pro-inflammatory mediators than 3R4F smoke. Although THS2.2 exposure elicited alterations in the gene expression, a higher transcriptome-induced biological impact was observed following 3R4F smoke: The effects of THS2.2 aerosol exposure, if observed, were mostly transient and diminished more rapidly after exposure than those of 3R4F smoke. The study demonstrated that the systems toxicology approach can reveal changes at the cellular level that would be otherwise not detected from functional assays, thus increasing the sensitivity to detect potential toxicity of a treatment/exposure.

中文翻译：

---

改良风险烟草产品气雾剂和卷烟烟雾对人类器官型小气道培养物的比较作用：系统毒理学方法

使用体外人类小气道上皮模型，我们评估了来自候选改良风险烟草产品烟草加热系统（THS）2.2的气溶胶的生物影响，以调查与香烟烟雾。按照医学研究所和烟草产品评估协会的建议，在该建议中，应与标准常规产品相比进行改良风险烟草产品评估，然后将THS2.2气溶胶暴露对小气道培养物的影响与3R4F香烟烟雾。我们使用了系统毒理学阐明毒性作用的方法不仅来自功能测定的读数，而且还来自组学技术。细胞毒性，纤毛跳动功能，促炎性介质的分泌和组织学评估代表功能测定。组学数据包括转录组和miRNA谱。从转录组数据计算暴露引起的因果生物网络扰动。结果表明，与3R4F烟相比，以测试剂量暴露于THS2.2气溶胶引起的细胞毒性水平降低，分泌的促炎性介质的变化降低。尽管THS2.2暴露引起了基因表达的改变，但在3R4F烟后观察到了更高的转录组诱导的生物学影响：THS2.2气溶胶暴露的影响（如果观察到），与3R4F烟雾相比，它们在暴露后大多是短暂的，并且消散速度更快。该研究表明，系统毒理学方法可以揭示细胞水平的变化，而这些变化本来无法从功能测定中检测到，从而提高了检测治疗/暴露潜在毒性的敏感性。