Cells were stained for nuclei (DAPI, white colored), MPO (green), H3Cit (red), and SARS-CoV-2 (Cyan). NETs released by SARS-CoV-2Cactivated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental part of NETs in the pathophysiology of COVID-19. Consequently, the inhibition of NETs represents a potential restorative target for COVID-19. Graphical Abstract Open Taranabant ((1R,2R)stereoisomer) in a separate window Intro The coronavirus disease 2019 (COVID-19) became pandemic, influencing more than 4 million people worldwide, with more than 300,000 deaths by May 2020. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19 resembles influenza, having a medical picture ranging from slight top airway symptoms in the majority of cases to severe lower airway symptoms inside a subgroup of individuals, in which acute respiratory distress syndrome develops and may rapidly progress to respiratory failure due to intense acute lung injury, its major cause of death (Lai et al., 2020). Taranabant ((1R,2R)stereoisomer) It is also known that this subgroup of individuals offers cytokine storm syndrome, which seems to be responsible for multi-organ failure (Chen et al., 2020). In addition, COVID-19 individuals develop signs and symptoms much like those observed in sepsis, many of which result in microthrombosis, organ dysfunction, and eventually shock (Wu and McGoogan, 2020; Magro et al., 2020; Guan et al., 2020). The first step in SARS-CoV-2 illness is the molecular connection between disease membrane glycoprotein spike (S) and the angiotensin-converting enzyme 2 (ACE2), which is definitely expressed in the several sponsor cells, including lung pneumocytes, VEGFA epithelial cells, and endothelial cells (Qi et al., 2020; Lovren et al., 2008). To total the fusion process, S protein needs to become cleaved by serine proteases such as TMPRSS2 (Shulla et al., 2011; Hoffmann et al., 2020). The improved quantity of circulating neutrophils has been described as an indication of the severity of respiratory symptoms and a poor medical end result in COVID-19 (Guan et al., 2020). Among effector mechanisms of neutrophils in inflammatory diseases, neutrophil-derived extracellular traps (NETs) are some of the most important (Brinkmann et al., 2004; Papayannopoulos and Zychlinsky, 2009; Kaplan and Radic, 2012; Jorch and Kubes, 2017). NETs are networks of extracellular materials composed of DNA comprising histones and granule-derived enzymes, such as myeloperoxidase (MPO) and elastase (Brinkmann et al., 2004). The process of Online formation by neutrophils, called NETosis, has been widely studied. In general, the process starts with neutrophil activation by pattern acknowledgement receptors or chemokines, followed by ROS production and calcium mobilization, which leads to the activation of protein arginine deiminase 4 (PAD-4), an intracellular enzyme involved in the deimination of arginine residues on histones (Li et al., 2010). In 2004, Brinkmann et al. (2004) in the beginning explained NETs as microbicidal mechanisms released by neutrophils (Brinkmann et al., 2004). However, accumulating evidence shown that NETs have double-edgedCsword activities. Besides their microbicidal activity, NETs have also been implicated in cells injury and, as a result, in the pathogenesis of several diseases, including rheumatoid arthritis (Khandpur et al., 2013; Sur Chowdhury et al., 2014), diabetes (Wong et al., 2015), and sepsis. Concerning sepsis, our group while others have explained that during experimental and medical sepsis, NETs are found in high concentrations in the blood and are positively correlated with Taranabant ((1R,2R)stereoisomer) biomarkers of vital organ accidental injuries and sepsis severity. Furthermore, disruption or inhibition of NET launch by pharmacological treatment with recombinant human being DNase (rhDNase) or PAD-4 inhibitors, respectively, markedly reduced organ damage, especially in the lungs, and improved the survival rate of severe septic mice (Coln et al., 2019; Czaikoski et al., 2016; Kambas et al., 2012; Martinod et al., 2015; Altrichter et al., 2010; Clark et al., 2007). The well-known similarities between sepsis and important events involved in.