Macrophage-exacerbated viral lung injury and mechanical overdistension-driven bacterial superinfection replicated in a human lung chip

These complications are often exacerbated in patients undergoing mechanical ventilation. Leveraging an immune-competent human lung alveolus-on-a-chip (Lung Chip) lined by human pulmonary alveolar epithelium co-cultured with monocyte-derived macrophages and interfaced with lung microvascular endothelium, we show that monocyte-derived macrophages play a central role in driving key hallmarks of severe influenza, including activated cell death programs.

Physiological strain mimicking breathing motions supported alveolar homeostasis, whereas pathological strain analogous to mechanical ventilator-induced lung overdistension promoted secondary Pseudomonas aeruginosa infection. Computational gene network analysis combined with experimental validation identified SIRT1 as a key modulator of inflammation and susceptibility to bacterial superinfection, which can be mitigated using pharmacological SIRT1 activators.