Novaes Silva, Maria ClaraRodríguez Hakim, MarianaThompson, BenjaminWagner, NormanHermans, ElineDupont, LievenVermant, Jan2025-10-232025-10-232025-09-24Novaes-Silva MC, Rodríguez-Hakim M, Thompson BR, Wagner NJ, Hermans E, Dupont LJ, Vermant J. How sighing regulates pulmonary surfactant structure and its role in breathing mechanics. Sci Adv. 2025 Sep 26;11(39):eadx6034. doi: 10.1126/sciadv.adx60342375-2548https://doi.org/10.1126/sciadv.adx6034https://hdl.handle.net/20.500.14468/30587The registered version of this article, first published in “Sci Adv. 2025 , vol. 11, 2025", is available online at the publisher's website: AAAS, https://doi.org/10.1126/sciadv.adx6034La versión registrada de este artículo, publicado por primera vez en “Sci Adv. 2025 , vol. 11, 2025", está disponible en línea en el sitio web del editor: AAAS, https://doi.org/10.1126/sciadv.adx6034Proyecto investigación: PID2023-147948OB-C33, Ministerio de Ciencia, Innovación y Universidades, the Agencia Estatal de Investigación (AEI, 10.13039/501100011033), and the European Social Fund Plus (FSE+)No. REGAGE21e00018555755, Ayudas María Zambrano para La Atracción de Talento Internacional, Ministerio de Ciencia, Innovación y Universidades (MICIU) and NextGenerationEUPulmonary 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.eninfo:eu-repo/semantics/openAccess22 Físicaartículo