Neutrophil Extracellular Traps (NETs), Immunothrombosis and the Microvascular Siege in Sepsis-ARDS

Sepsis-associated acute respiratory distress syndrome (ARDS) remains associated with substantial mortality despite decades of research, and the reasons why many disease-modifying treatments have failed remain incompletely understood. This narrative review synthesizes emerging evidence implicating neutrophil extracellular traps (NETs) in the interaction between innate immunity, immunothrombosis, and microvascular failure in sepsis-ARDS. NETs, extruded lattices of DNA, histones, and granular enzymes, serve as antimicrobial scaffolds but may contribute to tissue injury when excessive or persistent. Within the pulmonary microcirculation, experimental studies indicate that NETs can concentrate tissue factor and proteases, activate platelets, suppress fibrinolysis, and injure endothelium through histone cytotoxicity, supporting a self-amplifying thrombo-inflammatory loop. These processes may contribute to microvascular obstruction and barrier dysfunction, although their relative importance varies across experimental models and patient populations. We critically evaluate emerging NET-directed interventions, including peptidylarginine deiminase 4 (PAD4) inhibition to prevent NET formation, recombinant deoxyribonuclease (DNase) to dismantle existing scaffolds, targeted neutralization of NET components (citrullinated histones), and selective anticoagulation targeting factor XII/XI. Challenges of timing, infection risk, and patient heterogeneity support further evaluation of biomarker-guided "NET-otyping" using plasma myeloperoxidase-DNA, citrullinated histone H3, and experimental molecular imaging. Building on existing work in microvascular protection, we examine whether more effective and selective NET targeting could improve treatment of sepsis-ARDS. Clinical benefit remains to be established.