A comprehensive review published in Burns & Trauma on 15 June 2026 highlights the critical role of neutrophils and neutrophil extracellular traps (NETs) in ischaemia–reperfusion injury (IRI), a damaging second wave that can occur when blood flow is restored to tissues after events such as heart attack, stroke, or transplantation. The review, authored by researchers from Chongqing University Central Hospital, Chongqing University, University Hospital Essen, University of Duisburg-Essen, and Ludwig-Maximilians-University Munich, systematically examines how NETs contribute to IRI across the heart, brain, kidney, liver, lung, and transplanted organs.
IRI is a shared pathological process in conditions like myocardial infarction, ischaemic stroke, acute kidney injury, lung injury, and graft dysfunction. While rapid reperfusion is essential 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, arrive early at injured sites and release inflammatory mediators, proteases, and NETs. These web-like structures, composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase (NE), and other granular proteins, are designed to trap microbes during infection, but in sterile injury, excessive NET formation can damage endothelial cells, promote microthrombus formation, and sustain inflammatory feedback loops.
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. Once activated, neutrophils release NETs that can intensify inflammation, block microvessels, and spread injury across organs. The authors discuss the "NET–organ axis," where NET-driven inflammation and thrombosis extend damage beyond the original injury site, contributing to multiple organ dysfunction syndrome (MODS).
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. 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 rather than simple inflammatory debris, and their effects depend on timing, tissue context, and the balance between host defense and tissue damage. The therapeutic goal, they argue, 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 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.
These findings may inform future strategies for reducing reperfusion-related injury in cardiovascular disease, stroke, transplantation, and critical care. The review was funded by the Natural Science Foundation of Chongqing, China; the Science and Technology Research Program of Chongqing Municipal Education Commission; and the National Natural Science Foundation of China. More information is available at Chuanlink Innovations.
