Proteinase release from activated neutrophils in mechanically ventilated patients with non-COVID-19 and COVID-19 pneumonia

Seren, Seda; Derian, Lohann; Keleş, Irem; Guillon, Antoine; Lesner, Adam; Gonzalez, Loïc; Baranek, Thomas; Si‐Tahar, Mustapha; Marchand-Adam, S.; Jenne, Dieter E.; Paget, Christophe; Jouan, Youenn; Korkmaz, Brice

doi:10.1183/13993003.03755-2020

Cited by 35 publications

(29 citation statements)

References 15 publications

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“…Although the relative abundance of immune cells may vary across the upper and lower airways, previous studies observe a correlation between paired ETA and BALF samples. In addition, these studies show that ETA samples are not inherently neutrophilic 78 , though neutrophilia/granulocytosis may be a shared feature of non-COVID-19 and COVID-19 ARDS 10, 79 . In any event, our study is one of the only known to date to employ integrated multi-omics single-cell investigation of immunity in exclusively Black/AA subjects, which are disproportionately burdened with severe disease and worse outcomes.…”

Section: Discussionmentioning

confidence: 79%

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Eddins

Yang

Kosters

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing COVID-19 pandemic have caused ~33 million cases and over 585,000 deaths in the United States alone. Troubling disparities in COVID-19-associated mortality emerged early, with nearly 70% of deaths being Black/African-American (AA) patients in some areas, yet targeted studies to delineate features of disease severity within this demographic are scant. Our multi-omics single-cell analyses of immune profiles from airways and matching blood samples of Black/AA patients revealed pronounced pulmonary neutrophilia and low viral burden as a hallmark of severe disease, where neutrophil phenotypes display advanced features of cytokine release syndrome and acute respiratory distress syndrome (ARDS). Cell-cell communication and trajectory analysis reveal a subset of circulating S100A12+/CXCR4+ mature neutrophils that infiltrate the lung via the IL-8/CXCR2 axis. Recruited neutrophils progress toward a transcriptionally active and pathogenic state characterized by exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 along with elevated levels of neutrophil elastase and myeloperoxidase. Inflammatory monocytes recruited via neutrophil-derived CCL3/4 also produce elevated neutrophil chemotactic factor IL-8, potentiating the sustained neutrophilia in the airways. The IL-8/CXCR2 axis emerges as a potential therapeutic target to reduce pathogenic neutrophilia and constrain ARDS in severe COVID-19.

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Section: Discussionmentioning

confidence: 79%

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Eddins

Yang

Kosters

et al. 2021

Preprint

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“…NE is a serine protease stored within the primary granules of neutrophils. Compared to the levels recorded for HCs, both the concentration and activity of NE has been found to be significantly higher in blood samples from severe COVID-19 patients with ARDS and/or patients with disease severities ranging from mild to fatal (26,122,133,134). When released into plasma, NE is rapidly inactivated by endogenous protease inhibitors.…”

Section: Degranulationmentioning

confidence: 75%

Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets

Hazeldine

Lord

2021

Front. Immunol.

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Whilst the majority of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative pathogen of COVID-19, experience mild to moderate symptoms, approximately 20% develop severe respiratory complications that may progress to acute respiratory distress syndrome, pulmonary failure and death. To date, single cell and high-throughput systems based analyses of the peripheral and pulmonary immune responses to SARS-CoV-2 suggest that a hyperactive and dysregulated immune response underpins the development of severe disease, with a prominent role assigned to neutrophils. Characterised in part by robust generation of neutrophil extracellular traps (NETs), the presence of immature, immunosuppressive and activated neutrophil subsets in the circulation, and neutrophilic infiltrates in the lung, a granulocytic signature is emerging as a defining feature of severe COVID-19. Furthermore, an assessment of the number, maturity status and/or function of circulating neutrophils at the time of hospital admission has shown promise as a prognostic tool for the early identification of patients at risk of clinical deterioration. Here, by summarising the results of studies that have examined the peripheral and pulmonary immune response to SARS-CoV-2, we provide a comprehensive overview of the changes that occur in the composition, phenotype and function of the neutrophil pool in COVID-19 patients of differing disease severities and discuss potential mediators of SARS-CoV-2-induced neutrophil dysfunction. With few specific treatments currently approved for COVID-19, we conclude the review by discussing whether neutrophils represent a potential therapeutic target for the treatment of patients with severe COVID-19.

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“…Elastin-degrading (and other extracellular matrix protein–degrading) proteases released by neutrophils could contribute to alveolar damage, resulting in protein-rich alveolar edema ( 45 , 46 ). Neutrophil elastase, proteinase 3, cathepsin G, and activated cathepsin C have been detected in endotracheal aspirates of mechanically ventilated patients with ARDS associated or not associated with COVID-19 ( 47 ). We did not measure significant differences in neutrophil elastase concentrations between COVID-19 and influenza BAL fluid.…”

Section: Discussionmentioning

confidence: 99%

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza

et al. 2022

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Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected bronchoalveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated patients with influenza, as a non–COVID-19 viral pneumonia cohort. Compared with those of patients with influenza, BAL fluids of patients with COVID-19 contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1 β , IL-1RA, IL-17A, TNF- α , and G-CSF; the chemokines CCL7, CXCL1, CXCL8, CXCL11, and CXCL12 α ; and the protease inhibitors elafin, secretory leukocyte protease inhibitor, and tissue inhibitor of metalloproteinases 1. In contrast, α -1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotic treatment for bacterial coinfections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes, and NK cells were detected in patients with COVID-19 whereas concentrations tended to decrease in patients with influenza, highlighting the persistent immunological response to coinfections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.

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Proteinase release from activated neutrophils in mechanically ventilated patients with non-COVID-19 and COVID-19 pneumonia

Cited by 35 publications

References 15 publications

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients

Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza

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