Neutrophil Extracellular Traps Emerge as Organ-Specific Drivers and Therapeutic Targets in Ischaemia–Reperfusion Injury
核心洞察
A comprehensive review published in Burns & Trauma systematically examines how neutrophil extracellular traps (NETs) contribute to ischaemia–reperfusion injury (搜索) across the heart, brain, kidney, liver, lung, and transplanted organs.
NETs are dynamic immune structures whose harmful effects depend on timing, tissue context, and the balance between host defense and tissue damage, rather than being uniformly destructive.
Biomarkers such as cell-free DNA, citrullinated histone H3, and MPO–DNA complexes may help monitor disease severity and guide therapeutic response in IRI.
Restoring blood flow after a heart attack, stroke, or organ transplantation can paradoxically trigger a second wave of tissue damage—and a new review identifies the immune system's own neutrophil extracellular traps (NETs) as central mediators of this process. Published on 15 June 2026 in Burns & Trauma, the review from researchers at Chongqing University Central Hospital (搜索), University Hospital Essen (搜索), University of Duisburg-Essen, and Ludwig-Maximilians-University Munich (搜索) systematically maps how NETs drive ischaemia–reperfusion injury (搜索) (IRI) across multiple organ systems, offering a framework for organ-specific biomarkers and stage-targeted therapies.
The review, published under DOI 10.1093/burnst/tkag022, argues that NETs are not simply inflammatory debris but dynamic immune structures whose effects shift depending on the organ, disease stage, and local microenvironment. "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," the authors stated.
A Cross-Organ Perspective on Reperfusion Injury
IRI is a shared pathological process in myocardial infarction (搜索), ischaemic stroke (搜索), acute kidney injury (搜索), lung injury, and graft dysfunction after transplantation. Although rapid reperfusion remains essential for tissue survival, sudden oxygen restoration can activate sterile inflammation, reactive oxygen species (ROS) production, endothelial dysfunction, and immunothrombosis. Neutrophils arrive early at injured sites and release inflammatory mediators, proteases, and NETs—web-like structures composed of decondensed DNA, histones, myeloperoxidase (搜索) (MPO), neutrophil elastase (搜索) (NE), and other granular proteins.
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. 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.
Organ-Specific Mechanisms of NET-Mediated Damage
A key strength of the review is its cross-organ analysis. 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.
The review also introduces the concept of a "NET–organ axis," in which NET-driven inflammation and thrombosis extend damage beyond the original injury site and contribute to multiple organ dysfunction syndrome (搜索) (MODS). This systemic perspective underscores why localised ischaemic events can trigger remote organ failure.
Biomarkers for Monitoring and Stratification
The authors highlight several biomarkers that may help monitor disease severity and therapeutic response in NET-mediated IRI. These include cell-free DNA (cfDNA), citrullinated histone H3 (CitH3), and myeloperoxidase (搜索)–DNA (MPO–DNA) complexes. Such biomarkers could enable clinicians to identify patients with excessive NET activity and guide the timing of targeted interventions.
Therapeutic Strategies and the Path to Clinical Translation
The review outlines several potential approaches for reducing reperfusion-related injury. These include limiting harmful neutrophil recruitment, blocking peptidyl arginine deiminase 4 (搜索) (PAD4)-dependent NET formation, reducing ROS-driven activation, modulating complement-related pathways, and accelerating NET clearance with deoxyribonuclease I (DNase I)-based therapies.
However, the authors caution that clinical translation will require organ-specific biomarkers, careful timing, and strong safety evaluation, because NETs also support antimicrobial defense. Broad immune suppression could leave patients vulnerable to infection, making precise, stage-specific intervention essential. With better patient stratification, NET-targeted therapies may offer a practical route to protecting organs after reperfusion across cardiovascular disease, stroke, transplantation, and critical care settings.