Mechanotransducer Piezo1 drives ventilator‑induced lung injury in lung epithelial cells via the calcineurin/NFATc3 pathway

Ventilator‑induced lung injury (VILI) is a serious complication of mechanical ventilation (MV). The mechanosensitive ion channel Piezo1 converts mechanical forces into biochemical signals; however, its specific role in the pathogenesis of VILI remains unclear. The present study aimed to investigate the role of Piezo1 in lung epithelial cells in mediating VILI and its downstream signalling mechanisms. To this end, the current study utilized a murine VILI model established by high tidal volume MV, lung epithelial‑specific Piezo1 knockout mice, and in vitro cyclic stretch of mouse lung epithelial (MLE‑12) cells combined with genetic knockdown or pharmacological inhibition of Piezo1. Immunofluorescence and immunohistochemical analyses revealed that Piezo1 protein expression was significantly upregulated in the lung epithelium in vivo. Lung epithelial‑specific Piezo1 knockout mice exhibited markedly attenuated MV‑induced lung injury, barrier dysfunction and inflammatory responses. In vitro, cyclic mechanical stretch similarly upregulated Piezo1 expression in mouse lung epithelial MLE‑12 cells, accompanied by cytoskeletal disruption, and release of proinflammatory cytokines IL‑6, TNF‑α and IL‑1β, as assessed using ELISA. Genetic knockdown or pharmacological inhibition of Piezo1 effectively alleviated these injury phenotypes. Mechanistically, Piezo1 activation mediated stretch‑induced CA²⁺ influx, which triggered Calcineurin activation and subsequent nuclear translocation of the transcription factor NFATc3, ultimately driving the release of proinflammatory cytokines, including IL‑6, TNF‑α and IL‑1β. In conclusion, the results of the present study revealed a novel Piezo1/CA²⁺/Calcineurin/NFATc3 signalling axis that drives pulmonary epithelial inflammation and barrier dysfunction in VILI, suggesting that Piezo1 and its downstream signalling molecules are potential therapeutic targets.