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RATIONALE No in vivo data are available about the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). OBJECTIVES To characterize the changes in surfactant composition, function and structure during the early phase of meconium injury. METHODS We designed a translational, prospective, cohort study on nonbronchoscopic bronchoalveolar lavages of neonates with severe MAS (n=14) or no lung disease (n=18). Surfactant lipids have been analysed by liquid chromatography-high resolution mass spectrometry. Secretory phospholipases A2 subtype-IB,-V and -X and surfactant protein-A were assayed by ELISA. Surfactant protein-B and -C were analysed by Western Blot both under non-reducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, while lung aeration was evaluated by semi-quantitative lung ultrasound. Surfactant nanostructure was studied with cryo-electron and atomic force microscopy. MAIN RESULTS Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by the sPLA2 hydrolysis were increased. Protein-B and -C were significantly increased together with some shorter immature forms of protein-B. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicles size, tridimensional complexity and compactness. CONCLUSIONS Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration, due to hydrolysis and inflammation and as a defensive response. This impairs both surfactant structure and function, finally resulting in a reduced lung aeration. These findings support the development of new surfactant protection and anti-inflammatory strategies for severe MAS.