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 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 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 Differential type I interferon response and primary airway neutrophil extracellular trap release in children with acute respiratory distress syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jocelyn R. Grunwell ◽  
Susan T. Stephenson ◽  
Ahmad F. Mohammad ◽  
Kaitlin Jones ◽  
Carrie Mason ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Tracheal Aspirate ◽  
Neutrophil Extracellular Trap ◽  
Interferon Response ◽  
Type I ◽  
Elevated Expression ◽  
Extracellular Trap

Abstract Acute respiratory distress syndrome (ARDS) is a heterogeneous condition characterized by the recruitment of large numbers of neutrophils into the lungs. Neutrophils isolated from the blood of adults with ARDS have elevated expression of interferon (IFN) stimulated genes (ISGs) associated with decreased capacity of neutrophils to kill Staphylococcus aureus and worse clinical outcomes. Neutrophil extracellular traps (NETs) are elevated in adults with ARDS. Whether pediatric ARDS (PARDS) is similarly associated with altered neutrophil expression of ISGs and neutrophil extracellular trap release is not known. Tracheal aspirate fluid and cells were collected within 72 h from seventy-seven intubated children. Primary airway neutrophils were analyzed for differential ISG expression by PCR, STAT1 phosphorylation and markers of degranulation and activation by flow cytometry. Airway fluid was analyzed for the release of NETs by myeloperoxidase-DNA complexes using an ELISA. Higher STAT1 phosphorylation, markers of neutrophil degranulation, activation and NET release were found in children with versus without PARDS. Higher NETs were detected in the airways of children with ventilator-free days less than 20 days. Increased airway cell IFN signaling, neutrophil activation, and NET production is associated with PARDS. Higher levels of airway NETs are associated with fewer ventilator-free days.

scholarly journals Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Asbjørn G. Petersen ◽  
Peter C. Lind ◽  
Anne-Sophie B. Jensen ◽  
Mark A. Eggertsen ◽  
Asger Granfeldt ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Primary Endpoint ◽  
Bronchoalveolar Lavage Fluid ◽  
Distress Syndrome ◽  
Pulmonary Hemorrhage ◽  
Lavage Fluid

Abstract Background Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio. Methods ARDS was induced in female pigs (42–49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h. Results Final senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar–capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid. Conclusions In summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

scholarly journals Analysis of the Cellular Composition of Bronchoalveolar Lavage in the Modeling and Treatment of Acute Respiratory Distress Syndrome in Biomodel Mice

Biomeditsina ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. 17-22
Author(s):  
O. V. Alimkina ◽  
A. E. Petrenko ◽  
E. S. Savchenko ◽  
N. S. Ogneva ◽  
L. A. Taboyakova ◽  
...  
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Distress Syndrome ◽  
Simultaneous Increase ◽  
Single Administration ◽  
Cellular Composition ◽  
Over Time

This article investigates changes in the cellular composition of bronchoalveolar lavage over time in the modeling of acute respiratory distress syndrome (ARDS) in mice, followed by a single administration of Leutragine. In intact animals, macrophages predominate in bronchoalveolar lavage, which is the physiological norm. When modeling ARDS, neutrophils increase. A single administration of Leutragine leads to a significant reduction in the number of neutrophils and a simultaneous increase in macrophages in 72 hours, thus bringing the cellular composition of lavage to normal.

scholarly journals Cytological analysis of the lung material of C57BL/6Y mice in the simulation of acute respiratory distress syndrome

Biomeditsina ◽  
2021 ◽  
Vol 17 (3E) ◽  
pp. 17-22
Author(s):  
O. V. Alimkina ◽  
A. E. Petrenko
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Bronchoalveolar Lavage ◽  
Blood Cells ◽  
Distress Syndrome ◽  
White Blood Cells ◽  
Intact Group ◽  
Significant Difference ◽  
Over Time

The work is devoted to the study of changes in the cellular composition of bronchoalveolar lavage over time in the modeling of acute respiratory distress syndrome (ARDS) in mice. ARDS was modeled by administering α-galactosylceramide and a mixture of lipopolysaccharide with a complete Freud’s adjuvant. After euthanasia, bronchoalveolar lavage was taken for analysis. On this basis, changes in the total number of white blood cells, the percentage of neutrophils and macrophages were assessed. It was found that the percentage of neutrophils in the ARDS group shows a statistically significant difference from that in the intact group, starting from 3 hours after modeling ARDS. Further, a statistically significant decrease in macrophages was observed. 

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