BACKGROUND: Mechanical ventilation (MV) can induce or exacerbate ventilator-induced lung injury (VILI), particularly in mechanically heterogeneous lungs with pre-existing injury. METHODS: We investigated VILI in a rat model of bleomycin-induced lung injury and compared it with healthy controls using a combined in-vivo and ex-vivo imaging approach. Previously acquired in-vivo data from four-dimensional (4D) phase-contrast synchrotron micro-computed tomography (micro-CT) and forced oscillation measurements showed increased lung elastance and reduced local acinar deformation in bleomycin-induced injured lungs at baseline and after injurious MV. To identify structural and mechanical correlates, we performed automated three-dimensional (3D) pore analysis and atomic force microscopy (AFM) on formalin-fixed, paraffin-embedded lung tissue, complemented by histology and spatial co-registration. RESULTS: Ex-vivo analysis revealed pronounced airspace enlargement after both injurious MV of healthy lungs, and in bleomycin-injured lungs with inflammation and early fibrotic changes, with the strongest cumulative effect in combined bleomycin and VILI. AFM demonstrated region-specific mechanical responses, and correlation analyses linked pore geometry and nanoscale stiffness to in-vivo lung mechanics. Spatial analysis further showed co-localization of VILI-associated airspace damage with injured regions. CONCLUSIONS: Extracellular matrix remodelling modifies the lung's response to injurious mechanical ventilation, with VILI-associated airspace damage preferentially co-localising with regions of pre-existing matrix injury. This multiscale correlative approach provides mechanistic insight into the interplay between lung injury and VILI and informs ventilation strategies in structurally altered lungs.
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