A Multi-Omics Network Identifies Neutrophil Elastase-Positive Extracellular Vesicles in Plasma of Alpha-1 Antitrypsin Deficient Individuals as Accelerants of Lung Inflammation

Metabolomic profiling revealed that these EV are enriched with pro-inflammatory metabolites linked to dysregulated signaling pathways. Integrated transcriptomic and metabolomic network analysis revealed that dysregulated neutrophil gene expression and signaling pathways reshape EV metabolic cargo, linking metabolic reprogramming to inflammatory signal transduction in AATD. Moreover, differentially expressed EV metabolites may modulate gene expression in EV recipient cells, further sustaining chronic inflammation in AATD.

These findings establish a mechanistic link between neutrophil gene dysregulation and EV-driven inflammatory signaling, revealing how metabolic reprogramming of EV cargo influences cellular crosstalk via cytokine and protease-mediated pathways. The observed upregulation of interferon, pattern recognition receptors, and cytokine-mediated signaling pathways in neutrophils suggests a potential feedback loop amplifying inflammation in AATD and COPD.