Abstract
Neutrophil extracellular traps (NETs), built from mitochondrial or nuclear DNA, proteinases, and histones, entrap and eliminate pathogens in the course of bacterial or viral infections. Neutrophils’ activation and the formation of NETs have been described as major risk factors for acute lung injury, multi-organ damage, and mortality in COVID-19 disease. NETs-related lung injury involves both epithelial and endothelial cells, as well as the alveolar-capillary barrier. The markers for NETs formation, such as circulating DNA, neutrophil elastase (NE) activity, or myeloperoxidase-DNA complexes, were found in lung specimens of COVID-19 victims, as well as in sera and tracheal aspirates obtained from COVID-19 patients. DNA threads form large conglomerates causing local obstruction of the small bronchi and together with NE are responsible for overproduction of mucin by epithelial cells. Various components of NETs are involved in the pathogenesis of cytokine storm in SARS-CoV-2 pulmonary disease. NETs are responsible for the interplay between inflammation and thrombosis in the affected lungs. The immunothrombosis, stimulated by NETs, has a poor prognostic significance. Better understanding of the role of NETs in the course of COVID-19 can help to develop novel approaches to the therapeutic interventions in this condition.
Highlights
neutrophil extracellular traps (NETs)—IntroductionNeutrophils are the first-line defense cells eliminating microorganisms through unspecific mechanisms, such as oxidative stress, and the production of various antimicrobial factors [1]
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It is estimated that 10–15% of patients with severe COVID-19 progressed to acute respiratory distress syndrome (ARDS) triggered by cytokine storm, due to overproduction of IL-6, IL-8, IL-10, IL-17, and TNFα [54]
Summary
Neutrophils are the first-line defense cells eliminating microorganisms through unspecific mechanisms, such as oxidative stress, and the production of various antimicrobial factors [1]. NETs are large, extracellular, web-like structures composed of DNA fibers decorated with various antimicrobial factors such as: citrullinated histones, defensins, neutrophil elastase (NE), and myeloperoxidase (MPO) [3,4]. NADPH oxidase (NOX) generates ROS production, which in turn induces migration of myeloperoxidase (MPO) and neutrophil elastase (NE) from azurophilic granules to the nucleus, where NE triggers histone degradation and chromatin decondensation, further enhanced by MPO [5]. ROS generation has been shown to be sufficient for NET formation only when following autophagy signaling pathways [8]. The requirement for both autophagy and NADPH-oxidase activity in the course of NETosis has recently been confirmed in Candida-albicans-induced NETs, as well as in sepsis-triggered NETosis [9]. Generation of ROS-independent NETs via Toll-like receptor 4 (TLR4) has been demonstrated in platelet-stimulated NETosis in the course of sepsis [10]
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