Restoring blood flow after a heart attack, stroke, or organ transplantation can paradoxically trigger a second wave of tissue damage, a phenomenon known as ischaemia–reperfusion injury (IRI). A comprehensive review published in Burns & Trauma on 15 June 2026 (DOI: 10.1093/burnst/tkag022) brings together evidence that neutrophils and the web-like structures they release—neutrophil extracellular traps (NETs)—are central players in this immune-driven process.
IRI is a shared pathological mechanism in myocardial infarction, ischaemic stroke, acute kidney injury, lung injury, and graft dysfunction after transplantation. Although rapid reperfusion is essential for tissue survival, the sudden return of oxygen triggers sterile inflammation, reactive oxygen species production, endothelial dysfunction, and immunothrombosis. Neutrophils arrive early at injured sites and release inflammatory mediators, proteases, and NETs. However, NETs are not uniformly harmful; their effects vary 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, while assessing their potential as biomarkers and therapeutic targets.
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 then release NETs composed of decondensed DNA, histones, myeloperoxidase (MPO), neutrophil elastase (NE), 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 worsen cardiomyocyte injury and post-reperfusion inflammation. In the brain, NET accumulation obstructs cerebral microvessels, disrupts the blood–brain barrier, and contributes 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 NETs are dynamic immune structures rather than simple inflammatory debris. Their effects depend on timing, tissue context, and the balance between host defense and tissue damage. 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.
These findings may inform future strategies for reducing reperfusion-related injury in cardiovascular disease, stroke, transplantation, and critical care. 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.
