Tissue-guided multi-omics profiling identifies extracellular vesicle biomarkers indicative of lung pathology in acute respiratory distress syndrome

BackgroundAcute respiratory distress syndrome (ARDS) remains a lethal inflammatory lung condition lacking reliable biomarkers that reflect lung-specific pathology. Extracellular vesicles (EVs) circulate systemically and may carry molecular signals from injured organs, but the correspondence between EV cargo and lung tissue alterations remains unclear. MethodsWe established aspiration-, lipopolysaccharide (LPS)-, and COVID-19-induced murine ARDS models and applied a tissue-guided multiomics framework integrating proteomic and metabolomic analyses of lung tissue and plasma-derived EVs to identify lung-originating circulating biomarkers. ResultsFour proteins--haptoglobin (HP), inter-alpha-trypsin inhibitor heavy chains 3 and 4 (ITIH3, ITIH4), and clusterin (CLU)--were consistently upregulated in both lung tissue and plasma EVs across all ARDS etiologies. Metabolomic integration revealed dysregulation of arachidonic acid metabolism as a unifying inflammatory axis. Multiomics network analysis further distinguished etiology-specific molecular programs, including glycolytic activation in aspiration-induced, platelet aggregation in LPS-induced, and vascular smooth muscle dysregulation in COVID-19-induced ARDS. ConclusionsThis study establishes a tissue-informed EV profiling framework that links local lung pathology to systemic molecular signatures, revealing HP, ITIH3, ITIH4, CLU, and arachidonic-acid-related metabolites as potential diagnostic markers for ARDS. These findings provide a foundation for developing clinically translatable, EV-based biomarker assays for early detection and molecular subtyping of lung injury.