Neutrophil Extracellular Traps in Sepsis

Abstract

Sepsis is the leading cause of death in critically ill patients in intensive care units. Early recognition of sepsis and proper therapy are essential to reduce patient mortality. Moreover, treatment options for this deleterious inflammatory response to infection are limited. Neutrophils play an essential role in the innate immune response, providing the first line of host defense. It has recently been shown that these cells can trap and kill microorganisms by releasing neutrophil extracellular traps (NETs) composed of chromatin and antimicrobial proteins. Although the beneficial role of NETs during infections has been demonstrated, there is increasing evidence that NETs and their components contribute to the pathogenesis of several diseases, including sepsis. The aim of this review was to summarize the current evidence implicating NETs, as well as their components, in the development of sepsis and to discuss their potential use as novel therapeutic targets and as prognostic markers in septic patients.

Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants

“…[14][15][16]35,36 Fibrinogen chains and von Willebrand factor (vWF) are additional up-regulated proteins in LOS + NEC pigs (Figure 2c), which have been reported to be involved in the interaction between activated neutrophils and platelets during systemic inflammation. 19,37,38 Functional analysis by the Reactome database showed key regulated pathways during LOS/NEC. The top 20 pathways (lowest FDR) are shown in Supplementary Table S1 with 8/20 pathways related to platelet activation, clot formation, immunity and inflammatory response.…”

“…DNA and histones) facilitate severe systemic inflammation and aggravate septic conditions. 18,19 Cell-free DNA (cfDNA) has been used as a surrogate marker of circulating NETs as cfDNA from other sources such as platelet, mitochondria or bacteria were negligible, especially in pathological conditions. [20][21][22] Elevated circulating cfDNA and neutrophil granule proteins have been suggested as early biomarkers for sepsis in adults, [23][24][25] and elimination of DNA by DNase treatment reduces sepsis severity and organ injury.…”

Propagation of thrombosis by neutrophils and extracellular nucleosome networks

“…In line with this, NET have been shown to foster the development of sepsis. 41 In particular, NET have been detected in several organs during sepsis, including lungs, or even circulating in the systemic blood stream. 42 Thus, in severe sepsis, the prothrombotic actions of NET may have deleterious side effects on the blood supply and functions of multiple organs.…”

“…[5][6][7][8]41,53,58,59,[61][62][63] Since nucleosomes are not only externalized by neutrophils but also by apoptotic and necrotic cells, and since the plasma levels of nucleosomes have been shown to be increased under various pathological conditions (e.g. ischemia/reperfusion, cancer), the diagnostic evaluation of nucleosome-driven thrombosis requires the use of additional markers.…”

Synergistic Aspects to Explain the Pathophysiology of Sepsis and Septic Shock-An Opinion

“…An outstanding new approach to explain the pathogenesis of septic shock in humans has recently emerged since neutrophil traps had been described [43,44] and histone released from activated neutrophils NETs was incriminated as the major cause of death in sepsis [45,46] presumably due to its high toxicity to endothelial cells. However, the possibility that concomitantly with the breakdown of the nuclei and the release of histone from neutrophils NETs, the cell also release into the surrounding media oxidants, scores of acid lysosomal hydrolases and cationic peptides is not considered.…”