A Novel Neutrophil Extracellular Traps (NETs) Assay Predicts DIC and Stratifies Patients with Sepsis for Anti-IL-8 Therapy

 

Neutrophils are the most abundant leukocytes in mammals and play a vital role in innate immune responses. The homeostasis of neutrophils is maintained by balancing their short life span in the circulation with their regulated release from the bone marrow. Neutrophils extrude a meshwork of chromatin fibers that are decorated with granule-derived antimicrobial peptides and enzymes, commonly known as neutrophil extracellular traps, or NETs. While NETs protect against infection, research has indicated that they are associated with a growing number of immune-mediated conditions. More specifically, NETs can cause harm by promoting intravascular coagulation and multi-organ failure (MOF) in animal models. Although increasingly considered as important therapeutic targets, there is no robust and specific measure of NETs formation to inform clinical care and enable precision medicine in intensive care unit (ICU) patients.

Simon Abrams, Ph.D., of the University of Liverpool in the United Kingdom stated on Monday during the Vascular Biology virtual session that the intent of their study was to establish a novel assay for measuring NETs and to assess its clinical significance. Abrams and team looked at adult ICU patients, along with mice models of sepsis. NETs were directly induced by heterologous healthy neutrophils incubated with plasma from ICU patients and stratified into one of four groups of NET formation: absent, mild, moderate, and strong. Strong NETs were predominantly in sepsis patients and associated with organ injury. The key learning was that NETs formation on ICU admission independently predicted disseminated intravascular coagulation (DIC) and mortality, while interleukin (IL)-8 levels were observed and associated with NETs formation. Inhibiting IL-8 significantly reduced NETs formation induced by septic patient plasma. Looking at the septic mice, NETs-positive staining was observed primarily in the lungs and could be monitored via the noninvasive assay.

Abrams remarked that the assay could guide clinical management and enable targeted and personalized treatment. IL-8 is a major driving factor of NETs in sepsis, with anti-IL-8 therapy significantly reducing NETs-induced organ damage and mortality in septic mice.

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