This study describes a complex human in vitro model for evaluating anti‐inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre‐clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co‐cultured with macrophages differentiated from the THP‐1 cell line, creating a physiological biological microenvironment. To mimic the three‐dimensional architecture and dynamic expansion and relaxation of the air‐blood‐barrier, they are grown on a stretchable microphysiological lung‐on‐chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti‐inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro‐inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS‐induced acute lung injury measured best with cytokine IL‐6 release; (2) an inflammation caused by LPS at ALI (air‐liquid interface) to investigate aerosolized anti‐inflammatory treatment, measured with chemokine IL‐8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing‐like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ‐induced inflammation.

中文翻译：

---

用于评估抗炎药物反应的可拉伸人肺芯片肺泡炎症模型


这项研究描述了一个复杂的人体体外模型，用于评估肺泡中的抗炎药物反应，这可能有助于减少药物开发临床前阶段的动物试验。该模型基于人肺泡上皮细胞系Arlo与THP-1细胞系分化的巨噬细胞共培养，创造了生理生物微环境。为了模仿三维结构以及气血屏障的动态扩张和松弛，它们生长在可拉伸的微生理肺芯片上。为了验证体外模型，开发了三种不同的方案来证明临床上确定的糖皮质激素的抗炎作用，以在不同的促炎刺激后减少某些炎症标志物：（1）模拟由细菌LPS（脂多糖）引起的炎症LPS 诱导的急性肺损伤最好通过细胞因子 IL-6 的释放来测量； (2) LPS 在 ALI（气液界面）引起的炎症，以研究雾化抗炎治疗，通过趋化因子 IL-8 释放进行测量； (3) 结合人类炎症细胞因子 TNFα 和 IFNγ 来模拟导致上皮屏障破坏的关键细胞因子风暴，从而可以测量上皮屏障的最终削弱或保护。在所有情况下，巨噬细胞的存在似乎对于介导肺泡上皮炎症变化至关重要。 LPS 诱导导致炎症变化，与拉伸条件无关。动态拉伸模拟类似呼吸的力学，对于 TNFα/IFNγ 诱导的炎症上皮屏障破坏的临床相关结果的体外建模至关重要。