Neutrophil Extracellular Traps Drive Reperfusion Injury Across Organs, New Review Finds

A comprehensive review published in Burns & Trauma on June 15, 2026, brings together evidence that neutrophils and the web-like structures they release—neutrophil extracellular traps (NETs)—play a central role in ischemia-reperfusion injury (IRI), a damaging second wave that can occur when blood flow is restored after a heart attack, stroke, or organ transplantation. The review, led by researchers from Chongqing University Central Hospital and international institutions, systematically examines how NETs intensify inflammation, block microvessels, damage endothelial barriers, and spread injury across organs, pointing to new biomarkers and therapeutic strategies.

IRI is a shared pathological process in myocardial infarction, ischemic stroke, acute kidney injury, lung injury, and graft dysfunction after transplantation. While rapid reperfusion is essential for tissue survival, the sudden return of oxygen can trigger sterile inflammation, reactive oxygen species production, endothelial dysfunction, and immunothrombosis. Neutrophils arrive early at injured sites and release inflammatory mediators, proteases, and NETs. However, the review notes that NETs are not uniformly harmful; their effects may differ by organ, disease stage, and local microenvironment, underscoring the need for organ-specific research on mechanisms, timing, and therapeutic windows.

The review explains that reperfusion injury often begins at the vascular interface. Damaged tissues and activated endothelial cells release damage-associated molecular patterns (DAMPs), cytokines, and chemokines, recruiting neutrophils into vulnerable microvessels. Activated neutrophils can then release NETs, composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase, and other granular proteins. While NETs help trap microbes during infection, excessive NET formation in sterile injury can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.

A key strength of the review is its cross-organ perspective. In the heart, NETs can worsen cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation may obstruct cerebral microvessels, disrupt the blood–brain barrier, and contribute to the mismatch between successful vessel reopening and poor neurological recovery. In the kidney and liver, NETs interact with tubular cells, hepatocytes, Kupffer cells, and sinusoidal endothelial cells, amplifying inflammation and graft dysfunction. The review also discusses the ‘NET–organ axis,’ in which NET-driven inflammation and thrombosis extend damage beyond the original injury site and contribute to multiple organ dysfunction syndrome (MODS).

Biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and myeloperoxidase–DNA (MPO–DNA) complexes may help monitor disease severity and therapeutic response. The authors emphasize that the therapeutic goal should not be to eliminate neutrophil function entirely but to identify when NET formation becomes excessive, where it causes the greatest harm, and how it can be safely controlled. This perspective could help move NET-targeted treatment from broad immune suppression toward more precise, stage-specific intervention.

Potential therapeutic approaches include limiting harmful neutrophil recruitment, blocking peptidyl arginine deiminase 4 (PAD4)-dependent NET formation, reducing ROS-driven activation, modulating complement-related pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies. However, the review stresses that clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation because NETs also support antimicrobial defense. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion.

The review is available at https://doi.org/10.1093/burnst/tkag022.

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