The study links neutrophil infiltration with COVID-19 symptoms in the lungs. A small known but potent role of hyperactive white blood cells known as neutrophils, the ability to form extracellular neutrophil networks (NETs), in organ damage and mortality in COVID-19, according to a study by the Network Consortium Can contribute
NET-forming neutrophils in cell culture. Note the ejected DNA strands (arrows). Scanning electron microscopy of neutrophils 3 h after plating and co-cultivation with 4T1 breast cancer cells. NET-forming neutrophils in cell culture. Note the ejected DNA strands (arrows).
Scanning electron microscopy of neutrophils 3 h after plating and co-cultivation with 4T1 breast cancer cells. Scale bar – 25 μm. Image credit: Barnes et al, doi: 10.1084 / jem.20200652. Patients with severe COVID-19 infection develop acute respiratory distress syndrome (ARDS), lung inflammation, thick mucus discharge from the airways, extensive lung damage, and blood clots.
This last stage of the disease is difficult to manage. In the worst cases, patients require aggressive mechanical ventilation, and even then, a large number of patients die. This new study suggests that the severity of COVID-19 may be due to neutrophils.
As part of the body’s immune system, neutrophils detect bacteria and can attack bacteria with a stained DNA network consisting of toxic enzymes, known as NET, to expel their DNA. These NETs can digest and digest unwanted pathogens, but in cases of ARDS, they cause damage to the lungs and other organs.
Given the apparent similarity between severe COVID-19 and the clinical presentation of other known diseases caused by NET, such as ARDS, we propose that additional NETs may play an important role in the disease, professor at the Feinstein Institute Bassi Barnes, leader and co-author of the study.
As samples become available from patients, it will be important to determine whether the presence of NET is associated with the severity of the disease and / or with the particular clinical characteristics of COVID-19.
In the lungs, net cystic fibrosis drives mucus buildup in patients’ airways. NETs also drive acute respiratory distress syndrome (ARDS) after a variety of inducers, including influenza. In the vascular system, NET atherosclerosis and aortic aneurysm, as well as thrombosis (especially microtrombosis), have devastating effects on organ function.
NETs were identified in 2004, but many scientists never heard of them. Most of the network researchers have worked online on other diseases, and when we started hearing about the symptoms of COVID-19 patients.
It seemed familiar, “Cold Spring Harbor Laboratory cancer biologist Dr. Mikayla Egable, senior AND co-author of the study. “We see serious lung damage in these patients known as ARDS.
Which is another serious problem caused by excess NET and seen in cases of severe flu,” co-author Dr. Said Jonathan Spicer, a center for thoracic surgeons at the Research Institute of McGass University and McGill University Health.
Furthermore, their airways are often full of thick mucus and, unlike more severe lung infections, these patients form small clots in their bodies at much higher rates than normal.
NETs have also been found in the blood of patients with sepsis or cancer, where they can facilitate the formation of such blood clots. The network consortium is now studying whether NET is a common feature in COVID-19 cases.
If the results suggest that excess NET causes severe symptoms of COVID-19, then a new treatment pathway can be deployed to help COVID-19 patients. Current treatments used in other NETs and neutrophil-induced diseases.
Such as cystic fibrosis, gout and rheumatoid arthritis, can reduce NET activity in patients with COVID-19, reducing the need for invasive mechanical ventilation. In the immediate battle to treat patients with COVID-19.
A group of eleven international medical research organizations are investigating whether overactive immune cells that produce extracellular neutrophil trap (NET) cause the most severe cases.
The consortium, called Networth, includes the Cold Spring Harbor Laboratory, the Feinstein Institutes of Medical Research and the Research Institute of the McGill University Health Center (RI-MUHC).
The image from the Cold Spring Harbor Laboratory, Northwell Health Feinstein Institutes for Medical Research, and the Logosoc article from the McGill University Health Center Research Institute is published today in the Journal of Experimental Medicine stating that infected patients severe by COVID-19 have acute respiratory distress.
Syndrome (ARDS). Lung inflammation, thick discharge of mucus from the airways, extensive lung damage, and blood clots. This last stage of the disease is difficult to manage. In the worst cases, patients require aggressive mechanical ventilation, and even then, a large number of patients die.
The network suggests that COVID-19’s severity may be due to overactive white blood cells known as neutrophils. As part of the body’s immune system, neutrophils detect bacteria and can attack bacteria with a stained DNA network consisting of toxic enzymes, known as NET, to expel their DNA.
These NETs can digest and digest unwanted pathogens, but in cases of ARDS, they cause damage to the lungs and other organs. Betsy Barnes, Ph.D, stated: “Given the apparent similarity between the clinical presentation of severe COVID-19 and other known NET-driven diseases, such as ARDS.
We propose that additional NETs play an important role in the disease. It may play Head and co-author of the article and professor at the Feinstein Institutes. As samples become available from patients, it will be important to determine if the presence of NET is associated with the severity of the disease.
And or with the particular clinical characteristics of COVID -19. “NETs were identified in 2004, but many scientists never heard of them. Most network researchers have worked online on other diseases, and when we started hearing about the symptoms of COVID-19 patients.
It seemed familiar, “Cold Spring Harbor Laboratory cancer biologist Mikayla Egable , PhD, Said, which coincides with the Network Research Group around COVID-19 and is the main and relevant author of the article. Representation of the human body with calls indicating multiple serious pathologies.
In the lungs, net cystic fibrosis drives mucus buildup in patients’ airways. NETs also drive acute respiratory distress syndrome (ARDS) after a variety of inducers, including influenza. In the vascular system, NET atherosclerosis and aortic aneurysm, as well as thrombosis (especially microtrombosis), have devastating effects on organ function. Bioendor was used to generate the illustration.
Jonathan Spicer, M.Ed., Ph.D., clinical scientist at RI-MUHC and assistant professor of surgery at McGill University, is a thoracic surgeon who has seen the devastating effects of COVID-19 infection on the side of bed. “We see serious lung damage in these patients known as ARDS, which is another serious problem caused by excess NET and seen in cases of severe flu,” he said.
Also, their airways are often full of thick mucus and, unlike more severe lung infections, these patients form small clots in their bodies at much higher rates than normal. NET has also been found in the blood of patients with sepsis or cancer, where they can facilitate the formation of such blood clots.
Researchers from eleven institutions in the network are studying whether NET is a common feature in COVID-19 cases. If your findings suggest that excess NET causes severe symptoms of COVID-19, then a new treatment route may be deployed to help COVID-19 patients.
Current treatments used in other NETs and neutrophil-induced diseases, such as cystic fibrosis, gout, and rheumatoid arthritis, can reduce NET activity in patients with COVID-19, reducing the need for invasive mechanical ventilation. The team’s article was published in the Journal of Experimental Medicine.
New research finds a connection between NET and the course of Covid-19’s more serious illness. “We found that patients with COVID-19 infection have high blood levels of the extracellular neutrophil plexus, also known as NET.
Which is a product of neotrophilic cell death known as netosis,” first author U (Ray) Xu, MD, He says. Michigan Medicine Rheumatologist. Zuo is a cardiologist and vascular medicine specialist at Michigan Medicine Franklin Cardiovascular Center, Yogen Kanthi, M.D.
And he worked in the study with Jason Knight, M.D., Ph.D., a Michigan Medicine rheumatologist, who studies inflammation and neutrophils. The researchers analyzed blood samples from 50 patients with COVID-19 for this publication.
In light of the COVID-19 epidemic, Zuo and colleagues say, there is an urgent need to better understand what can be caused by SARS-CoV-2 infection causing inflammatory storms and blood clots, a breathing storm. . It fails and leads to a mechanical ventilation requirement in many patients.
They believe that NET COVID-19 may be relevant to many aspects of research, since thrombosis and inflammation are characteristic of a serious infection. This is the first publication to come out of the Frank Impact CVC CV Impact Research Igniter Grant program, which was created to address COVID-19 from both a basic science and clinical point of view.
In patients with severe coronovirus 2019 disease (COVID-19 related pneumonia) and / or acute respiratory distress syndrome (ARDS), lung inflammation, thick mucus secretion in the airways, elevated serum proinflammatory cytokine levels, lung damage extensive and microthrombosis.
This late stage of the disease is difficult to manage and large numbers of patients die (Chen et al., 2020a, preprint; Wang et al., 2020; Zhao et al., 2020; preprint; Zheng et al., 2020 )). The severity of COVID-19, with its epidemic prevalence, has put unprecedented pressure on our health system, and treatment strategies are urgently needed.
Infection with acute acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, but it is a rapid and poorly understood host response involving cytokine storms that cause severe COVID-19 (Mehta et al, 2020). The onset and spread of cytokine storms is unclear.
We propose that the host response in patients with severe COVID-19 focuses on restricted activation of the most common leukocyte in peripheral blood: neutrophils. Neutrophilia predicts poor outcomes in patients with COVID-19 (Wang et al., 2020), and the ratio of neutrophils to lymphocytes is an independent risk factor for severe disease (Liu et al., 2020, preprint).
In addition, at autopsy of the lungs of three patients with COVID-19 in Weill Cornell therapy, we observed infiltration of neutrophils in the pulmonary capillaries, acute capillitis with deposition of fibrin, extravasation of neutrophils in the alveolar space, and neutrophilic mucositis.
Neutrophil infiltration was also observed in two recent reports on pathological findings of autopsy COVID-19 patients (Fox et al., 2020, preprint; Yao et al., 2020). Although leukocytosis and neutrophilia are signs of acute infection, in the case of COVID-19, we propose that neutrophilia may also be a source of extracellular extracellular traps (NETs) of additional neutrophils.
Net and disease: Neutrophils are recruited early at sites of infection, where they kill pathogens (bacteria, fungi, and viruses) through oxidative blasts and phagocytosis (Schönrich and Reffty, 2016). However, neutrophils have another much less recognized means of killing pathogens: NET formation (Brinkman et al., 2004).
Net DNA and proteins extracted from neutrophils have network-like structures that give rise to pathogens (Fig. 2). Ejecting DNA into outer space is not widely recognized as an important immune function. However, even plants have specialized cells that kill soil pathogens using this mechanism (Wen et al., 2009).
Net construction is a regulated process, although the signals involved are incompletely understood. The key enzymes in NET formation are: neutrophil elastase (NE), which breaks down intracellular proteins and triggers nuclear decay; Peptidyl arginine deaminase type 4 (PAD4), which citrils histones to facilitate the dissolution and release of chromosomal DNA; And gasdermine D.
Which produces pores in the membrane of neutrophils, facilitating the decomposition of the cell membrane and the expulsion of DNA and related molecules (Chen et al., 2018; Kaplan and Reddick, 2012; Papayannopoulos, 2018; Papayannopoulos et al ). it is. 2010; Rohrbach et al., 2012; Solberger et al., 2018).
Although NETs are beneficial in host defense against pathogens, collateral damage from sustained NET formation also stimulates many disease processes, even during viral infection (Schönrich & Rafti, 2016).
In fact, excessive NET formation can trigger a cascade of inflammatory responses that promote cancer cell metastasis, destroy surrounding tissue, facilitate microtrombosis, and the pulmonary, cardiac, and renal systems.
It causes permanent damage (Jörch and Cubes, 2017; Kesenbroek et al ;; 2009; Papayanopoulos, 2011ay; Figure 3). Importantly, these are the three organ systems commonly affected in severe COVID-19 (Bono et al., 2020; Chen et al., 2020b).
NET and ARDS: Previous reports link large-scale NET formation with lung diseases, especially ARDS. In fact, plasma NET levels are higher in patients with ARDS associated with transfusions than in subjects without ARDS (Corderier et al, 2012).
Furthermore, neutrophils appear to be “primed” to form NET in patients with ARDS associated with pneumonia, and both the degree of priming and the level of NET relative to blood are associated with the severity and mortality of the disease (Adrover et al ., 2020).
They are correlated with; 2019; Abrahami et al., 2018; Lefranais et al., 2018; Mikasic et al., 2018). Extracellular histones, possibly partially derived from NET, are advanced in bronchoalveolar lavage fluid and plasma from patients with ARCDS (Love et al., 2017).
Naked histones are toxic to cells, and there is strong experimental evidence supporting the role of histones in ARDS and sepsis (Vygrecka et al., 2017; Xu et al., 2015). Therefore, NETs, as sources of external histones, are likely to contribute to ARDS and sepsis (Chaput and Zychlinsky, 2009; Lefrançais and Looney, 2017; Xu et al., 2009).
In animal models of lung injury, NETs evolve in response to a variety of ARDS-inducing stimuli, and inhibiting or dissolving NET reduces lung injury and increases survival (Caudrillier et al., 2012; Lefrançais et al.) 2018; Liu et al. 2016; Narasaraju et al., 2011).
NET and cystic fibrosis (CF): the mucous secretions found in the airways of patients with COVID-19 (Mao et al. 2020, preprint) are reminiscent of those observed in patients with CF (Martinez-Alleman et al, 2017). The reason and origin of these secretions is unclear.
However, in CF, mucous secretions impair gas exchange and have been shown to involve extracellular DNA, in part due to NETs released in response to persistent lung infection. Furthermore, the excessive formation of NAS along the NE makes the mucus thicker and more viscous (Manzentreiter et al., 2012), not only inhibits ventilation, but also facilitates the colonization of bacteria.
Such colonization further promotes the recruitment of neutrophils and the formation of networks, which increases the viscosity of mucus and, consequently, reduces the patient’s respiratory function. If COVID-19 contains NET of mucous secretion, they can play a similar role in CF: impaired gas exchange and facilitate secondary infection.
Net and excessive thrombosis: Acute heart and kidney injuries are common in patients with severe COVID-19 and contribute to the death of the disease (Bono et al., 2020). D-dimer (an indicator of the fibrin degradation product of overactive coagulation) has become a reliable marker of severe COVID-19 (Zhou et al., 2020).
High levels of NET in the blood may explain these findings: Intravascular NETs have been shown to play an important role in the initiation and induction of thrombosis in arteries and veins (Fuchs et al., 2012).
For example, in severe coronary heart disease, NET complexes are elevated and NET levels are positively associated with thrombin levels, which predict adverse cardiac events (Borissoff et al., 2013). Furthermore, the autopsy obtained from septic patients suggests that NET infiltrates microthrombi (Jiménez-Alcazar et al., 2017).
Therefore, when networks are transmitted to high levels in the blood, they can trigger small vessel occlusion, causing damage to the lungs, heart, and kidneys (Cedarwell et al., 2015; Fuchs et al., 2010; Larten et al., 2019; Martinode and Wagner, 2014).
In a mouse sepsis model, intravascular NTSs form microthrombi that rupture blood vessels and damage the lungs, liver, and other organs (Jiménez-Alcázar et al., 2017). Mechanically, NET activates the coagulation contact pathway (also called plasma calicarin-kin system) through electrostatic interactions between NET histones and platelet phospholipids (Oehmcke et al., 2009).
Histones can also promote platelet activation by acting as ligands for toll-like receptors on platelets (Semero et al., 2011). At the same time, NE (which binds NET in its active form) probably also plays an important role in the digestion of the main coagulation inhibitors, antithrombin III and inhibitors of the tissue factor pathway (Massberg et al ., 2010).
Furthermore, there is almost certainly a feedback loop by which procoagulant activity (eg, that of thrombin) leads to platelet activation, and activated platelets are formed by NET formation (Corderillier et al., 2012; Clarke al-al, 2007) Et al., 2010; Masberg et al., 2010; Sriramkumar et al., 2014; Von Bruhl et al., 2012).
Normal perfusion of cardiac and renal microorganisms in trap and animal models (Seidell et al., 2015; Janson et al., 2017; Nakazawa et al., 2017; Raup-Consavage et al, 2018) dissolving with DNase. Restorations Based on the above findings, we argue that attacking intravascular NETs can reduce thrombosis in patients with severe COVID-19.
These inflammatory mediators regulate the activity of neutrophils and induce the expression of chemoattractants (molecules that increase the traffic of neutrophils to the sites of inflammation). Furthermore, severe lung injuries, ARDS, and death from cytokine storms (Channappanavar and Perman, 2017); Chasterman et al., 2017).
It is particularly notable that NET can induce macrophages to protect IL1 Not, and IL1 formation improves NET formation in various diseases, including aortic aneurysm and atherosclerosis (Kahlenberg) et al, 2013; Et al., 2015).
Together, these data suggest that under conditions where normal signals are lost to reduce inflammation, such as during cytokine storms, a signaling circuit between macrophages and neutrophils can cause uncontrollable and progressive inflammation.
In fact, there is an association between NET and IL1 in severe asthma (Lachowicz-Scroggins et al., 2019). If a looped NET-IL1 is activated in severe COVID-19, accelerated production of NET and IL1 NET can accelerate respiratory disruption, microthrombus formation, and exacerbated immune responses.
Importantly, IL1ly induces IL6 (Dinrello, 2009), and IL6 has become a promising target for COVID-19 treatment (Mehta et al., 2020; Xu et al., 2020, preprint). IL6 can signal through classical and trans signaling (Calaberry and Rose-John, 2014).
In classical signaling, IL6 binds to a complex of the IL6Rα transmembrane receptor with the common cytokine receptor gp130. In trans-signaling, soluble IL6Rα (sIL6Rα) binds to IL6 to initiate signaling through g130.
Trans signaling is strongly associated with proinflammatory states (Calaberry and Rose-John, 2014), and lower sIL6Rα levels are associated with better lung function, for example, asthma (Ferreira et al., 2013; Hawking et al. ) 2012).
Neutrophils can shed sIL6Rα in response to IL8 (Marin et al., 2002), which is abundant in cytokine storms associated with COVID-19 (Wu and Yang, 2020; Zhang et al., 2020). Together, these findings lead us to hypothesize that IL-6 trans-signaling.
Extensive infiltration of neutrophils in the pulmonary capillaries with acute capillitis with pulmonary deposition and extravasation in the alveolar space. An image was chosen to emphasize the capillary lesions. (B) Neutrophilic mucosa of the trachea.
The entire airway was affected (image by A. Borkuk, Weil Cornell Medical Center). Both samples come from a 64-year-old Hispanic man grown with diabetes, end-stage kidney disease on hemodialysis, heart failure, and hepatitis C on leadipasvir / sofosbuvir therapy.
He refused medical intervention, so he was not intubated and died in the emergency room 5 hours shortly after presentation, shortly after the fever developed. There was no evidence of sepsis clinically in this patient, premature cultures were negative.
And an autopsy was performed within 5 hours of death. Similar neutrophil distribution, but with less extensive infiltration, has been analyzed to date in two additional channels. These other two cases had a longer duration of symptoms.