scholarly journals Targeting potential drivers of COVID-19: Neutrophil extracellular traps

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Betsy J. Barnes ◽  
Jose M. Adrover ◽  
Amelia Baxter-Stoltzfus ◽  
Alain Borczuk ◽  
Jonathan Cools-Lartigue ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Distress Syndrome ◽  
Cytokine Production ◽  
Neutrophil Extracellular Traps ◽  
Organ Damage ◽  
Clinical Severity ◽  
Pulmonary Diseases ◽  
Cytokine Storm ◽  
Extracellular Traps ◽  
Autopsy Specimen

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10–15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils—the ability to form neutrophil extracellular traps (NETs)—may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.

scholarly journals Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome

Blood ◽  
2020 ◽  
Vol 136 (10) ◽  
pp. 1169-1179 ◽  
Author(s):  
Elizabeth A. Middleton ◽  
Xue-Yan He ◽  
Frederik Denorme ◽  
Robert A. Campbell ◽  
David Ng ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Ex Vivo ◽  
Neutrophil Extracellular Traps ◽  
Dna Complexes ◽  
Platelet Factor ◽  
Extracellular Traps ◽  
Fraction Of Inspired Oxygen

Abstract COVID-19 affects millions of patients worldwide, with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens, and they can trigger immunothrombosis. We studied the connection between NETs and COVID-19 severity and progression. We conducted a prospective cohort study of COVID-19 patients (n = 33) and age- and sex-matched controls (n = 17). We measured plasma myeloperoxidase (MPO)-DNA complexes (NETs), platelet factor 4, RANTES, and selected cytokines. Three COVID-19 lung autopsies were examined for NETs and platelet involvement. We assessed NET formation ex vivo in COVID-19 neutrophils and in healthy neutrophils incubated with COVID-19 plasma. We also tested the ability of neonatal NET-inhibitory factor (nNIF) to block NET formation induced by COVID-19 plasma. Plasma MPO-DNA complexes increased in COVID-19, with intubation (P < .0001) and death (P < .0005) as outcome. Illness severity correlated directly with plasma MPO-DNA complexes (P = .0360), whereas Pao2/fraction of inspired oxygen correlated inversely (P = .0340). Soluble and cellular factors triggering NETs were significantly increased in COVID-19, and pulmonary autopsies confirmed NET-containing microthrombi with neutrophil-platelet infiltration. Finally, COVID-19 neutrophils ex vivo displayed excessive NETs at baseline, and COVID-19 plasma triggered NET formation, which was blocked by nNIF. Thus, NETs triggering immunothrombosis may, in part, explain the prothrombotic clinical presentations in COVID-19, and NETs may represent targets for therapeutic intervention.

scholarly journals Pentoxifylline as a Potential Adjuvant Therapy for COVID-19: Impeding the Burden of the Cytokine Storm

2021 ◽  
Vol 10 (22) ◽  
pp. 5305
Author(s):  
Wiktoria Feret ◽  
Magdalena Nalewajska ◽  
Łukasz Wojczyński ◽  
Wojciech Witkiewicz ◽  
Patrycja Kłos ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Adjuvant Therapy ◽  
Distress Syndrome ◽  
Pulmonary Diseases ◽  
Cytokine Storm ◽  
A2a Receptor ◽  
Potential Benefits ◽  
Immunomodulatory Properties ◽  
Adenosine A2a

The outburst of inflammatory response and hypercoagulability are among the factors contributing to increased mortality in severe COVID-19 cases. Pentoxifylline (PTX), a xanthine-derived drug registered for the treatment of vascular claudication, has been reported to display broad-spectrum anti-inflammatory and immunomodulatory properties via adenosine A2A receptor (A2AR)-related mechanisms, in parallel to its rheological actions. Prior studies have indicated the efficacy of PTX in the treatment of various pulmonary diseases, including the management of acute respiratory distress syndrome of infectious causes. Therefore, PTX has been proposed to have potential benefits in the treatment of SARS-CoV-2 symptoms, as well as its complications. The aim of this review is to discuss available knowledge regarding the role of PTX as a complementary therapeutic in SARS-CoV-2.

scholarly journals Neutrophil extracellular traps persist at high levels in the lower respiratory tract of critically ill COVID-19 patients

2021 ◽  
Author(s):  
Werner J D Ouwendijk ◽  
Matthijs P Raadsen ◽  
Jeroen J A van Kampen ◽  
Robert M Verdijk ◽  
Jan H von der Thusen ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Tract ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Critically Ill ◽  
Inflammatory Markers ◽  
Lower Respiratory Tract ◽  
Distress Syndrome ◽  
Neutrophil Extracellular Traps ◽  
Extracellular Traps

Abstract SARS-CoV-2 induced lower respiratory tract (LRT) disease can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill COVID-19 patients. Plasma NET levels peaked early after ICU admission and correlated with SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma. Baseline plasma NET quantity correlated with disease severity, but was not associated with soluble markers of thrombosis nor with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from fatal COVID-19 patients. Thus, NETs are produced and retained in the LRT of critical COVID-19 patients and could contribute to SARS-CoV-2-induced ARDS pathology.  

scholarly journals Neutrophil Extracellular Traps Are Elevated in Patients with Pneumonia-related Acute Respiratory Distress Syndrome

2019 ◽  
Vol 130 (4) ◽  
pp. 581-591 ◽  
Author(s):  
Inès Bendib ◽  
Luc de Chaisemartin ◽  
Vanessa Granger ◽  
Frédéric Schlemmer ◽  
Bernard Maitre ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Distress Syndrome ◽  
Neutrophil Extracellular Traps ◽  
Neutrophil Extracellular Trap ◽  
Enzyme Linked Immunosorbent Assay ◽  
Extracellular Traps ◽  
Extracellular Trap

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Neutrophil extracellular traps have been associated with tissue damage. Whether these are involved in the pathogenesis of human acute respiratory distress syndrome (ARDS) and could be a potential therapeutic target is unknown. The authors quantified bronchoalveolar and blood neutrophil extracellular traps in patients with pneumonia-related ARDS and assessed their relationship with ventilator-free days. Methods Immunocompetent patients with pneumonia and moderate or severe ARDS (n = 35) and controls (n = 4) were included in a prospective monocentric study. Neutrophil extracellular trap concentrations were quantified (as DNA–myeloperoxidase complexes) in bronchoalveolar lavage fluid and serum by enzyme-linked immunosorbent assay. The relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and the primary clinical endpoint (i.e., the number of live ventilator-free days at day 28) was assessed using linear regression analyses. Results There was no significant relationship between bronchoalveolar lavage neutrophil extracellular trap concentrations and ventilator-free days by multiple regression analysis (β coefficient = 2.40; 95% CI, −2.13 to 6.92; P = 0.288). Neutrophil extracellular trap concentrations were significantly higher in bronchoalveolar lavage than in blood of ARDS patients (median [first to third quartiles]:154 [74 to 1,000] vs. 26 [4 to 68] arbitrary units, difference: −94; 95% CI, −341 to −57; P < 0.0001). Bronchoalveolar concentrations of patients were higher than those of controls (154 [74 to 1,000] vs. 4 [4 to 4] arbitrary units, difference: −150; 95% CI, −996 to −64; P < 0.001) and associated with bronchoalveolar interleukin-8 (Spearman’s ρ = 0.42; P = 0.012) and neutrophil concentrations (ρ = 0.57; P < 0.0001). Intensive care unit mortality (12%, n = 2 of 17 vs. 17%, n = 3 of 18; P > 0.99) and the number of ventilator-free days at day 28 (22 [14 to 25] vs. 14 [0 to 21] days; difference: −5; 95% CI, −15 to 0; P = 0.066) did not significantly differ between patients with higher (n = 17) versus lower (n = 18) bronchoalveolar neutrophil extracellular trap concentrations. Conclusions Bronchoalveolar neutrophil extracellular trap concentration was not significantly associated with mechanical ventilation duration in pneumonia-related ARDS.

scholarly journals The Combined Use of Leutragin and Pulmonary Surfactant-BL Increases Animal Survival in a Model of Fatal Acute Respiratory Distress Syndrome

Biomeditsina ◽  
2020 ◽  
Vol 16 (4) ◽  
pp. 52-59
Author(s):  
V. N. Karkischenko ◽  
I. A. Pomytkin ◽  
M. T. Gasanov ◽  
O. I. Stepanova ◽  
R. A. Klesov ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Pulmonary Surfactant ◽  
Distress Syndrome ◽  
Cytokine Production ◽  
Cytokine Storm ◽  
Risk Of Death ◽  
Animal Survival ◽  
Combined Use

This study aims to investigate effects of leutragin — a stabilized analogue of the endogenous hexapeptide dynorphin 1-6 — in combination with pulmonary surfactant-BL on animal survival in an experimental fatal model of “cytokine storm” and acute respiratory distress syndrome (ARDS) in C57Bl/6Y mice. Compared to the control, administration of leutragin and pulmonary surfactant-BL in a combined regimen led to a statistically significant increase in the survival rate and a decrease in the risk of death in animals with ARDS. It was shown that the suppression of proinflammatory cytokine production in the lungs with a simultaneous replenishment of the endogenous surfactant with an exogenous pulmonary surfactant is a promising new pharmacological approach to the treatment of ARDS accompanied by a “cytokine storm”.

scholarly journals Acute respiratory distress syndrome caused by carbon monoxide poisoning and inhalation injury recovered after extracorporeal membrane oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column: a case report

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Ji Hoon Jang ◽  
Hang Jea Jang ◽  
Hyun-Kuk Kim ◽  
Jin Han Park ◽  
Hyo-Jung Kim ◽  
...  
Keyword(s):  
Carbon Monoxide ◽  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Carbon Monoxide Poisoning ◽  
Polymyxin B ◽  
Inhalation Injury ◽  
Cytokine Storm ◽  
Direct Hemoperfusion

Abstract Background Inhalation injury from smoke or chemical products and carbon monoxide poisoning are major causes of death in burn patients from fire accidents. Respiratory tract injuries from inhalation injury and carbon monoxide poisoning can lead to acute respiratory distress syndrome and cytokine storm syndrome. In the case of acute respiratory failure needing mechanical ventilation accompanied by cytokine storm, mortality is high and immediate adequate treatment at the emergency department is very important. Case presentation This report describes a case of acute respiratory distress syndrome and cytokine storm followed by carbon monoxide poisoning in a 34-year-old Korean male patient who was in a house fire, and was successfully treated by extracorporeal membrane oxygenation and direct hemoperfusion with polymyxin B-immobilized fiber column at emergency department. Conclusions To prevent mortality in acute respiratory distress syndrome with cytokine storm from inhalation injury and to promote a better prognosis, we suggest that early implication of extracorporeal membranous oxygenation along with direct hemoperfusion with polymyxin B-immobilized fiber column even at the emergency department should be considered.

scholarly journals Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis

PLoS ONE ◽  
2016 ◽  
Vol 11 (2) ◽  
pp. e0148142 ◽  
Author(s):  
Paula Giselle Czaikoski ◽  
José Maurício Segundo Correia Mota ◽  
Daniele Carvalho Nascimento ◽  
Fabiane Sônego ◽  
Fernanda Vargas e Silva Castanheira ◽  
...  
Keyword(s):  
Neutrophil Extracellular Traps ◽  
Organ Damage ◽  
Clinical Sepsis ◽  
Extracellular Traps

Cytokine storm syndrome in SARS-CoV-2: a review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Braira Wahid ◽  
Noshaba Rani ◽  
Muhammad Idrees
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Failure ◽  
Severe Acute Respiratory Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Cytokine Storm ◽  
Global Level ◽  
Management Option ◽  
Human Contact

Abstract After wreaking havoc on a global level with a total of 5,488,825 confirmed cases and 349,095 deaths as of May 2020, severe acute respiratory syndrome coronavirus 2 is truly living up to the expectations of a 21st-century pandemic. Since the major cause of mortality is a respiratory failure from acute respiratory distress syndrome, the only present-day management option is supportive as the transmission relies solely on human-to-human contact. Patients suffering from coronavirus disease 2019 (COVID-19) should be tested for hyper inflammation to screen those for whom immunosuppression can increases chances of survival. As more and more clinical data surfaces, it suggests patients with mild or severe cytokine storms are at greater risk of failing fatally and hence these cytokine storms should be targets for treatment in salvaging COVID-19 patients.

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