Conclusion
In summary, our study is the first to utilize organ-on-a-chip and organoid technologies, optimizing both the smoke generation process and chip design to create a model that closely replicates contemporary fire-related smoke-induced lung injury. By integrating advanced technologies such as proteomics and computational biology, alongside organoid technology and animal models, we identified potential pathogenic pathways and genes. Simultaneously, various cell types’ responses to smoke injury were analyzed at the organ level, and potential therapeutic drugs and combinations were screened. This approach provides a powerful tool for studying the mechanisms and developing treatments for fire-related SI-ALI. However, there are areas for improvement in our study. First, the chip model primarily focuses on early lung injury, neglecting late-stage pathologies such as fibroblast activation and extracellular matrix deposition that may occur following smoke exposure. These factors can contribute to the development of pulmonary fibrosis, significantly impairing respiratory function and affecting patients’ quality of life, with currently no effective treatments available. Therefore, future research should delve deeper into the mechanisms of pulmonary fibrosis induced by smoke exposure. Additionally, while the results obtained from the A549 cell line were validated using lung organoids, future studies should consider employing primary lung epithelial cells to more authentically replicate the pathophysiological processes of the lung. Furthermore, the bidirectional flow provided by the perfusion system, along with the absence of neutrophils in the immune cell population, may influence the model’s injury responses, warranting further optimization in subsequent research. Lastly, this study did not incorporate mechanical stretching of the lung. Previous research indicates that respiratory motion can affect the pathophysiological processes of the lung barrier[62], and rapid breathing can lead to shear stress[61] injuries during smoke exposure, potentially exacerbating lung damage. This complexity may complicate the investigation of mechanisms related to smoke-induced toxicity. Consequently, a static model was selected for this study. Future research will build upon these findings to further investigate the mechanisms of smoke-induced lung injury under conditions of respiratory motion.