A comprehensive review published in Burns & Trauma on 15 June 2026 systematically examines how neutrophils and neutrophil extracellular traps (NETs) contribute to ischemia–reperfusion injury (IRI) across multiple organs, including the heart, brain, kidney, liver, lung, and transplanted organs. The work, conducted by researchers from Chongqing University Central Hospital, University Hospital Essen, and other institutions, highlights NETs as dynamic immune structures that can either protect or harm depending on timing and tissue context. The review underscores the potential for NET-targeted therapies to mitigate reperfusion-related damage in cardiovascular disease, stroke, and critical care.
IRI occurs when blood flow is restored after a period of ischemia, paradoxically causing additional tissue damage. This process is a common pathological feature in myocardial infarction, ischemic stroke, acute kidney injury, and graft dysfunction after transplantation. While rapid reperfusion is essential for tissue survival, the sudden reintroduction of oxygen can trigger sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils, as first responders, release inflammatory mediators and NETs—web-like structures composed of decondensed DNA, histones, myeloperoxidase (MPO), and neutrophil elastase (NE). Although NETs are beneficial for trapping microbes during infection, excessive NET formation in sterile injury can damage endothelial cells, promote microthrombus formation, and sustain inflammatory loops.
The review provides a cross-organ perspective on NET-mediated IRI. In the heart, NETs exacerbate cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation obstructs cerebral microvessels and disrupts the blood–brain barrier, contributing 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," where NET-driven inflammation and thrombosis extend damage beyond the original injury site, potentially leading to multiple organ dysfunction syndrome (MODS). Biomarkers such as cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and MPO–DNA complexes may help monitor disease severity and therapeutic response.
The authors emphasize that NETs should not be viewed as simple inflammatory debris but as dynamic structures whose effects depend on the balance between host defense and tissue damage. Therapeutic strategies should aim not to eliminate neutrophil function entirely but to identify when NET formation becomes excessive 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 pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies. However, clinical translation requires organ-specific biomarkers, careful timing, and robust safety evaluation, as NETs also support antimicrobial defense. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion.
