Multi-dimensional plasma proteomic profiling elucidates molecular mechanisms and pathophysiological networks in pediatric severe traumatic brain injury

Background
Severe traumatic brain injury (sTBI) is a leading cause of trauma-related mortality and morbidity in pediatric populations. The heterogeneous progression of sTBI presents significant challenges for prognosis and pathophysiological investigation, necessitating advances beyond traditional approaches. This study utilized plasma proteomic profiling to identify sTBI-specific protein alterations and functional pathways correlating with clinical variables in pediatric patients.

Methods
We performed plasma proteomic analysis on 20 matched pairs of pediatric sTBI patients and healthy controls. Proximity extension assays quantified 1,472 proteins. Gene set enrichment analysis identified enriched Reactome pathways and Gene Ontology terms among differentially expressed proteins. Pathway-clinical variable associations were calculated using weighted correlation sums between pathway proteins and clinical variables. Protein-protein interaction networks were analyzed using STRING.

Results
Using significance thresholds of FDR-adjusted P < 0.05 and fold change ≥ 4, we identified 65 differentially expressed proteins between sTBI samples and controls. Analysis revealed proteins involved in neuroinflammation and upregulated pathways related to cytokine and receptor/ligand signaling. Altered protein expression indicated structural and functional changes in neurons, glial cells, and vasculature. Upregulated pathways positively correlated with injury severity score, hyperglycemia, and coagulopathy, while negatively correlating with vault skull fractures and acidosis. IL-6 emerged as a central hub in protein-protein interactions, with distinct clusters representing opsonization, TNF family signaling, amidation, neuronal/astrocyte injury, and multifaceted sTBI responses.ConclusionsThese findings identify differentially expressed plasma proteins and enriched signaling pathways associated with clinical features, providing novel insights into pediatric sTBI pathophysiology. The identification of IL-6 as a central hub protein and the correlation of specific pathways with injury severity, metabolic dysfunction, and coagulopathy suggest potential targets for therapeutic intervention and prognostic biomarker development. This proteomic approach advances our understanding of the complex molecular cascades underlying pediatric sTBI and may inform precision medicine strategies for improved patient outcomes.