How sighing regulates pulmonary surfactant structure and its role in breathing mechanics.

Pulmonary surfactants reduce the work of breathing, enhance compliance, and prevent alveolar collapse. Yet, their role extends beyond that of a simple surfactant; otherwise, exogenous surfactant therapy would fully restore compliance in acute respiratory distress syndrome (ARDS) by increasing surface concentration alone. Here, we show that interfacial microstructure and mechanics, regulated by spontaneous or ventilator-induced sighs, play a critical role. Using interfacial rheometry and structural analysis, including in situ neutron reflectometry and Raman-based techniques, we find that sighs enrich the air-liquid interface with saturated lipids, triggering structural rearrangements. This periodic "reset" transforms the layer into a mechanically robust, DPPC-rich film, where compressional hardening counteracts tension. These findings highlight the nonequilibrium dynamics of surfactant layers and underscore the importance of interfacial compressive stresses, not just tension, in governing lung mechanics. This mechanism helps sustain low interfacial stress and high compliance, offering mechanistic insight to guide protective ventilation strategies upon lung trauma and possibilities to optimize surfactant-enabled pulmonary treatment.