Abstract
BackgroundRecent studies have suggested that excessive formation of neutrophil extracellular traps (NETs) plays a critical role in the pathogenesis of sepsis. Although elevation of the plasma level of cell-free DNA (cf-DNA) has been reported in sepsis patients, there has been little direct measurement of circulating free NETs such as myeloperoxidase-conjugated DNA (MPO-DNA). The objectives of this study were to detect NETs in the bloodstream of patients with septic shock, and to assess the correlations of circulating NET levels with organ dysfunction, disease severity, and mortality.MethodsFifty-five patients with septic shock admitted to the intensive care units (ICUs) of 35 Japanese hospitals were studied. Septic shock was diagnosed according to the 1997 definition of the American College of Chest Physicians/Society of Critical Care Medicine. To detect circulating NETs, plasma levels of MPO-DNA and cf-DNA were measured by sandwich enzyme-linked immunosorbent assay and by fluorometric assay on days 1, 3, and 7 after the onset of septic shock. Physiological and mortality data were collected from the clinical database.ResultsOn days 1, 3, and 7, the patients showed a marked increase in plasma MPO-DNA levels compared with healthy volunteers, whereas the plasma cf-DNA level was only increased significantly on day 1 and then decreased rapidly. A high MPO-DNA level on days 3 and 7 were associated with 28-day mortality.On days 3 and 7, the MPO-DNA levels were inversely correlated with both the mean arterial pressure and the PaO2/FIO2 ratio, whereas the cf-DNA level was not correlated with either parameter. There was a positive correlation between the plasma MPO-DNA level and the sepsis-related organ failure assessment score on days 3 and 7. Neither cf-DNA nor MPO-DNA levels were correlated with the disseminated intravascular coagulation (DIC) score or the platelet count.ConclusionThe increase in circulating MPO-DNA in patients with septic shock indicates acceleration of NET formation in the early stages of sepsis. High MPO-DNA levels are associated with the severity of organ dysfunction and 28-day mortality due to septic shock, but not with the DIC score. These results suggest that excessive NET formation contributes to the pathogenesis of septic shock.
Highlights
Recent studies have suggested that excessive formation of neutrophil extracellular traps (NETs) plays a critical role in the pathogenesis of sepsis
Gram-negative bacilli were isolated from 33 patients, gram-positive cocci were detected in 14 patients, and Candida albicans was found in 1 patient
The myeloperoxidase-conjugated DNA (MPO-DNA) level was closely related to 28-day mortality and to markers of the severity of organ dysfunction, including the P/F ratio, Mean arterial pressure (MAP), and Sepsis-Related Organ Failure Assessment (SOFA) score
Summary
Recent studies have suggested that excessive formation of neutrophil extracellular traps (NETs) plays a critical role in the pathogenesis of sepsis. Numerous biomarkers [4] are frequently used to predict morbidity and mortality in patients with sepsis, including acute-phase proteins such as procalcitonin, C-reactive protein, inflammatory cytokines and chemokines, cell surface proteins of inflammatory cells, and coagulation markers. While these physiological scores and biomarkers are useful, novel biomarkers that can achieve more reliable early diagnosis and assist therapeutic decision making are urgently needed. Neutrophil extracellular traps (NETs) are a potential biomarker for sepsis because neutrophils are the most abundant of the leukocytes and play a central role in the pathogenesis of sepsis. Neutrophils attack extracellular microbes by releasing toxic proteins and enzymes, including myeloperoxidase (MPO), neutrophil elastase (NE), and defensins, from their granules through the process of degranulation [5]
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