Extracellular Vesicle Lipid Cargo Orchestrates Lung Inflammation and Resolution

Extracellular vesicles (EVs) are increasingly recognized as critical mediators of intercellular communication, transferring a diverse repertoire of proteins, nucleic acids, and bioactive lipids that modulate the functional phenotype of recipient cells in both paracrine and endocrine manner. While the roles of EV-transported microRNAs (miRs) and proteins in pulmonary diseases have been extensively studied, the contribution of EV-encapsulated bioactive lipid mediators to the pathophysiology of pulmonary disorders, including acute respiratory distress syndrome (ARDS), remains largely underexplored. Here, we review the biosynthesis of bioactive lipids, their incorporation into EVs, and their roles in regulating pulmonary inflammation, injury, and resolution. We first highlight upstream signaling pathways, such as toll-like receptor 4 (TLR4) and the nuclear factor of activated T-cells cytoplasmic member 3 (NFATc3), which regulate the expression of lipid biosynthetic enzymes. We then examine how EV-encapsulated pro-inflammatory and pro-resolving lipids contribute to ARDS pathogenesis and clinical outcomes. Evidence supporting the role of EV-transported pro-resolving lipid mediators as key regulators of inflammation resolution and restoration of pulmonary homeostasis is also reviewed, along with their therapeutic potential in mitigating ARDS. Finally, we identify critical gaps in our understanding of how EV lipids modulate ARDS pathophysiology and discuss the challenges and opportunities for therapeutic targeting.