Plasma regulates homeostatic pulmonary endothelial signaling to mitigate vascular leak following polytrauma and hemorrhagic shock.

Introduction: In hemorrhagic shock, plasma resuscitation preserves vascular integrity and protects against trauma-induced coagulopathy and organ injury. Despite demonstrated clinical benefit, the endothelial mechanisms underlying plasma resuscitation remain incompletely defined. This study investigated endothelial-specific responses to plasma resuscitation to identify targetable pathways that promote vascular repair after traumatic injury. Methods: A murine model of severe polytrauma-hemorrhagic shock (PT/HS) with demonstrable vascular endotheliopathy by 24 hours was used to compare pulmonary vascular endothelial cell (EC) responses to resuscitation with lactated Ringer's (LR) relative to fresh frozen plasma (FFP). Whole blood was collected for inflammatory biomarker analysis, and pulmonary vascular leak was quantified by dextran extravasation. Pulmonary EC glycocalyx (eGC) structure was assessed by transmission electron microscopy and immunofluorescence. Spatial transcriptomic profiling of pulmonary ECs was performed using a GeoMx Digital Spatial Profiler. Key transcriptomic findings related to mitochondrial biogenesis were validated by immunostaining and by treating primary human lung EC with FFP or LR. Results: At 24 hours after injury, FFP reduced systemic inflammatory cytokines, pulmonary innate immune cell infiltration, and PT/HS-induced vascular leak compared to LR. Plasma levels of syndecan-1, syndecan-4, and hyaluronan were decreased, consistent with enhanced pulmonary eGC expression. Although few differences in eGC-related genes were detected, pathway analysis revealed enrichment of cellular bioenergetics and metabolic recovery pathways in ECs after FFP, whereas LR was associated with oxidative stress and inflammatory signaling. FFP enhanced mitochondrial content in pulmonary EC after PT/HS and in treated human EC compared to LR-treated controls. Conclusions: FFP resuscitation after PT/HS reduces systemic inflammation and preserves pulmonary vascular barrier function, potentially through promotion of mitochondrial signaling, metabolic recovery, and endothelial stress regulation.