A new review published in Burns & Trauma synthesizes evidence that neutrophil extracellular traps (NETs) are central to the tissue damage that occurs when blood flow is restored after ischemia. The review, led by researchers from Chongqing University Central Hospital, University Hospital Essen, and Ludwig-Maximilians-University Munich, examines how NETs amplify inflammation, block microvessels, and damage endothelial barriers across multiple organs, including the heart, brain, kidney, liver, and lung.
Ischemia-reperfusion injury (IRI) is a common pathological process in myocardial infarction, ischemic stroke, acute kidney injury, and graft dysfunction after transplantation. While timely reperfusion is critical for tissue survival, the sudden return of oxygen can trigger sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils, the immune system's first responders, release NETs—web-like structures composed of DNA, histones, and granular proteins like myeloperoxidase and neutrophil elastase. Excessive NET formation in sterile injury can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.
The review's cross-organ perspective reveals that NETs exacerbate cardiomyocyte injury in the heart, obstruct cerebral microvessels and disrupt the blood-brain barrier in the brain, and interact with tubular cells and hepatocytes in the kidney and liver, amplifying inflammation and graft dysfunction. The authors describe a "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 NETs are dynamic immune structures whose effects depend on timing, tissue context, and the balance between host defense and tissue damage. Therapeutic strategies should aim to control excessive NET formation rather than eliminate neutrophil function entirely. Potential approaches include blocking peptidyl arginine deiminase 4 (PAD4)-dependent NET formation, reducing ROS-driven activation, modulating complement pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies.
Clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation, as NETs also support antimicrobial defense. The review, titled "Neutrophils and neutrophil extracellular traps in organ ischemia-reperfusion injury: a review," was published in Burns & Trauma on 15 June 2026 and is available at https://doi.org/10.1093/burnst/tkag022. The research was supported by the Natural Science Foundation of Chongqing, China (Grant No. CSTB2025NSCQ-GPX1056), among other funding sources.
