Experimental model of ventilator-induced lung injury induces proteomic signatures of neurodegeneration in the hippocampus

Abstract

Abstract Background Mechanical ventilation is associated with acute and long-term cognitive dysfunction, yet the molecular pathways linking ventilator-induced lung injury (VILI) to brain injury remain poorly characterized. We previously demonstrated that peripheral IL-6 signaling mediates delirium-like phenotypes in a murine VILI model. Here, we use unbiased aptamer-based proteomics to determine whether this model exhibits proteomic signatures consistent with neurodegenerative processes in the brain and plasma. Methods C57BL/6 mice were subjected to VILI via high tidal volume mechanical ventilation or served as spontaneously breathing (SB) controls. Brain tissue (hippocampal and cortical regions) and plasma were analyzed using the SomaScan proteomic platform (10,778 and 7,307 proteins, respectively). Differential expression, hierarchical clustering, principal component analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify dysregulated proteins, functional networks, and predicted upstream regulators. Results SomaScan proteomics identified 253 and 995 significantly altered proteins ( p < 0.05) between VILI and SB mice in cortical and hippocampal regions, respectively, and 290 in plasma. Hippocampal pathway analysis revealed enrichment of neurodegeneration, cognitive impairment, and neural differentiation/maturation categories, with dysregulation of proteins including CSNK2A1, SNCA, BDNF, PLD3, and TMEM240. Predicted upstream regulators included CTNNB1, NR3C1, SNCA, and PPARGC1A. Plasma proteomics identified coordinated shifts in metabolic, inflammatory, and vascular injury pathways consistent with an IL-6-associated acute phase response, with predicted activation of HNF4A and PPARG. Only 9 proteins, including PLD3, HAVCR2 (TIM-3), MAG, and STMN4, were dysregulated across all three compartments, with brain-restricted proteins MAG and STMN4 detectable in plasma. The hippocampal region demonstrated the most pronounced alterations, underscoring region-specific vulnerability. Conclusions VILI induced a dominant hippocampal injury signature enriched for neurodegeneration, cognitive impairment, and disrupted neuronal maturation. Parallel plasma shifts were consistent with inflammatory–metabolic stress and identified a concurrent peripheral response potentially relevant to the lung–brain axis, while detection of brain-restricted proteins in plasma raises the possibility of blood–brain barrier compromise or CNS protein release. Together, these findings support a model in which peripheral lung injury activates coordinated peripheral and hippocampal neuroinflammatory pathways implicated in neurodegenerative biology.

The authors' abstract, as published at the source. Intensive Care Medicine Experimental, 2026 · DOI ↗