A comprehensive review published in Burns & Trauma on June 15, 2026, reveals that neutrophil extracellular traps (NETs) play a pivotal role in ischemia-reperfusion injury (IRI), a condition that paradoxically damages tissues when blood flow is restored after a heart attack, stroke, or transplantation. The review, conducted by researchers from Chongqing University Central Hospital, University Hospital Essen, and Ludwig-Maximilians-University Munich, synthesizes evidence showing that NETs—web-like structures released by neutrophils—can intensify inflammation, block microvessels, and spread injury across organs.
IRI is a shared pathological process in myocardial infarction, ischemic stroke, acute kidney injury, lung injury, and graft dysfunction. While rapid reperfusion is essential for tissue survival, sudden oxygen restoration can activate sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils are early responders at injured sites, releasing 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.
The review systematically examines how neutrophils and NETs contribute to IRI across the heart, brain, kidney, liver, lung, and transplanted organs. 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 poor neurological recovery despite successful vessel reopening. 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, contributing 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 therapeutic goals should not eliminate neutrophil function entirely but instead identify when NET formation becomes excessive, where it causes the greatest harm, and how it can be safely controlled. Potential 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, 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 full review is available at https://doi.org/10.1093/burnst/tkag022.
