The respiratory epithelium is intimately associated with the pathophysiologies of highly infectious viral contagions and chronic illnesses such as chronic obstructive pulmonary disorder, presently the third leading cause of death worldwide with a projected economic burden of £1.7 trillion by 2030. Preclinical studies of respiratory physiology have almost exclusively utilised non-humanised animal models, alongside reductionistic cell line-based models, and primary epithelial cell models cultured at an air-liquid interface (ALI). Despite their utility, these model systems have been limited by their poor correlation to the human condition. This has undermined the ability to identify novel therapeutics, evidenced by a 15% chance of success for medicinal respiratory compounds entering clinical trials in 2018. Consequently, preclinical studies require new translational efficacy models to address the problem of respiratory drug attrition. This review describes the utility of the current in vivo (rodent), ex vivo (isolated perfused lungs and precision cut lung slices), two-dimensional in vitro cell-line (A549, BEAS-2B, Calu-3) and three-dimensional in vitro ALI (gold-standard and co-culture) and organoid respiratory epithelium models. The limitations to the application of these model systems in drug discovery research are discussed, in addition to perspectives of the future innovations required to facilitate the next generation of human-relevant respiratory models.

呼吸道上皮细胞与高度传染性病毒传染和慢性疾病（如慢性阻塞性肺病）的病理生理学密切相关，慢性阻塞性肺病目前是全球第三大死亡原因，预计到 2030 年经济负担将达到 1.7 万亿英镑。呼吸生理学的临床前研究已经几乎完全使用非人源化动物模型，以及基于还原细胞系的模型，以及在气液界面 (ALI) 培养的原代上皮细胞模型。尽管它们很实用，但这些模型系统由于与人类状况的相关性较差而受到限制。这削弱了识别新疗法的能力，2018 年进入临床试验的药用呼吸化合物有 15% 的成功机会证明了这一点。因此，临床前研究需要新的转化功效模型来解决呼吸系统药物消耗的问题。这篇评论描述了当前的效用体内（啮齿动物）、离体（隔离灌注肺和精密切割肺切片）、二维体外细胞系（A549、BEAS-2B、Calu-3）和三维体外ALI（金标准和共培养）和类器官呼吸道上皮模型。除了对促进下一代与人类相关的呼吸模型所需的未来创新的看法外，还讨论了这些模型系统在药物发现研究中应用的局限性。