As demonstrated with a ventilator-induced ALI/ARDS model, the expression levels of Piezo1 and VE-cadherin are decreased in mouse and patient lung samples undergoing long-term ventilation, and Piezo1 activation by cycle stretch enhances calpain activity, which suppresses Src-mediated VE-cadherin phosphorylation and subsequently stabilizes VE-cadherin junctions. Here, SRC is linked to acute respiratory distress syndrome.