Role of Neutrophil Extracellular Traps in COVID-19 Progression: An Insight for Effective Treatment

Abstract

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

Oxidative Stress and Hyper-Inflammation as Major Drivers of Severe COVID-19 and Long COVID: Implications for the Benefit of High-Dose Intravenous Vitamin C

“…Excessive inflammation damages organs and the endothelium of the blood vessels. Endothelial damage and the formation of neutrophil extracellular traps (NET) favour (micro-)thromboses, which also severely impair organ function (Arcanjo et al, 2020;Ackermann et al, 2021;Blanch-Ruiz et al, 2021) and may also have impact on latent Long COVID complaints (Zhu et al, 2022).…”

Pathophysiological mechanisms of thrombosis in acute and long COVID-19

“…The cell-free DNA released in NETs provides a negatively charged surface to allow FXII binding and activation of the contact (intrinsic) coagulation pathway, resulting in microvascular occlusion ( 62 , 63 ). Additionally, neutrophil elastase (NE) and myeloperoxidase, two other components of NETs, can cleave and inactivate natural anticoagulants (TFPI and TM), thereby leading to a procoagulant shift of the hemostatic balance and local clot formation ( 54 , 64 ).…”

Butyrate: Connecting the gut-lung axis to the management of pulmonary disorders

“…The recruitment and activation of neutrophils and other innate immune cells is a major feature of COVID-19 induced ARDS with the formation of extracellular traps, and damage of the respiratory barrier with edema ( 130 – 132 ). Thus, neutrophils and other myeloid cells are being explored as potential therapeutic targets ( 133 ).…”