Background Exposure to air particulate matter (PM) is associated with various diseases in the human respiratory system. To date, most in vitro studies showing cellular responses to PM have been performed in cell culture using a single cell type. There are few studies considering how multicellular networks communicate in a tissue microenvironment when responding to the presence of PM. Here, an in vitro three-dimensional (3D) respiratory mucosa-on-a-chip, composed of human nasal epithelial cells, fibroblasts, and endothelial cells, is used to recapitulate and better understand the effects of urban particulate matter (UPM) on human respiratory mucosa. Results We hypothesized that the first cells to contact with UPM, the nasal epithelial cells, would respond similar to the tissue microenvironment, and the 3D respiratory mucosa model would be a suitable platform to capture these events. First, whole transcriptome analysis revealed that UPM induced gene expression alterations in inflammatory and adhesion-related genes in human nasal epithelial cells. Next, we developed an in vitro 3D respiratory mucosa model composed of human nasal epithelial cells, fibroblasts, and endothelial cells and demonstrated that the model is structurally and functionally compatible with the respiratory mucosa. Finally, we used our model to expose human nasal epithelial cells to UPM, which led to a disruption in the integrity of the respiratory mucosa by decreasing the expression of zonula occludens-1 in both the epithelium and endothelium, while also reducing vascular endothelial cadherin expression in the endothelium. Conclusions We demonstrate the potential of the 3D respiratory mucosa model as a valuable tool for the simultaneous evaluation of multicellular responses caused by external stimuli in the human respiratory mucosa. We believe that the evaluation strategy proposed in the study will move us toward a better understanding of the detailed molecular mechanisms associated with pathological changes in the human respiratory system.

中文翻译：

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使用全转录组分析和芯片上的器官识别城市颗粒物引起的人类呼吸道粘膜完整性破坏。

背景暴露于空气颗粒物 (PM) 与人类呼吸系统中的各种疾病有关。迄今为止，大多数显示细胞对 PM 反应的体外研究都是在使用单一细胞类型的细胞培养物中进行的。很少有研究考虑多细胞网络在响应 PM 的存在时如何在组织微环境中进行通信。在这里，由人鼻上皮细胞、成纤维细胞和内皮细胞组成的体外三维 (3D) 呼吸道黏膜芯片用于概括和更好地了解城市颗粒物 (UPM) 对人呼吸道黏膜。结果 我们假设第一个与 UPM 接触的细胞，即鼻上皮细胞，会与组织微环境相似的反应，3D 呼吸道黏膜模型将是捕捉这些事件的合适平台。首先，全转录组分析显示 UPM 诱导人鼻上皮细胞中炎症和粘附相关基因的基因表达改变。接下来，我们开发了由人鼻上皮细胞、成纤维细胞和内皮细胞组成的体外 3D 呼吸道粘膜模型，并证明该模型在结构和功能上与呼吸道粘膜兼容。最后，我们使用我们的模型将人鼻上皮细胞暴露于 UPM，通过降低上皮和内皮中 zonula occludens-1 的表达，同时降低血管内皮钙粘蛋白的表达，从而破坏呼吸道黏膜的完整性在内皮中。结论 我们证明了 3D 呼吸道粘膜模型作为一种有价值的工具的潜力，可用于同时评估人类呼吸道粘膜中外部刺激引起的多细胞反应。我们相信，研究中提出的评估策略将使我们更好地了解与人类呼吸系统病理变化相关的详细分子机制。