A comprehensive review published in Burns & Trauma on June 15, 2026, synthesizes evidence that neutrophils and the web-like structures they release, known as neutrophil extracellular traps (NETs), play a pivotal role in the damage that occurs when blood flow is restored to tissues after a heart attack, stroke, or organ transplantation. This phenomenon, called ischemia-reperfusion injury (IRI), paradoxically exacerbates tissue damage despite the necessity of reperfusion for tissue survival.
Researchers from Chongqing University Central Hospital, Chongqing University, University Hospital Essen, University of Duisburg-Essen, and Ludwig-Maximilians-University Munich examined how NETs contribute to IRI across the heart, brain, kidney, liver, lung, and transplanted organs. The review explains that upon reperfusion, damaged tissues release damage-associated molecular patterns (DAMPs) that recruit neutrophils. These activated neutrophils release NETs—composed of decondensed DNA, histones, myeloperoxidase, and neutrophil elastase—which can intensify inflammation, block microvessels, damage endothelial barriers, and spread injury to other organs, a phenomenon termed the "NET–organ axis."
In the heart, NETs worsen 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, and Kupffer cells, amplifying inflammation and graft dysfunction. The review notes that 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 with effects that 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 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.
The findings may inform future strategies for reducing reperfusion-related injury in cardiovascular disease, stroke, transplantation, and critical care. 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.
The review is published in Burns & Trauma with the DOI 10.1093/burnst/tkag022 and was supported by several Chinese funding agencies, including the Natural Science Foundation of Chongqing and the National Natural Science Foundation of China.
