Neutrophil Extracellular Traps in Fatal COVID-19-Associated Lung Injury.

Astrid Obermayer,Walter Stoiber,Jasmin D Haslbauer,Matthias S Matter,Lisa-Maria Jakob,Alexandar Tzankov,Robert Pichler

doi:10.1155/2021/5566826

Astrid Obermayer, Walter Stoiber + Show 5 more

Open Access

https://doi.org/10.1155/2021/5566826

Copy DOI

Abstract

An excess formation of neutrophil extracellular traps (NETs), previously shown to be strongly associated with cytokine storm and acute respiratory distress syndrome (ARDS) with prevalent endothelial dysfunction and thrombosis, has been postulated to be a central factor influencing the pathophysiology and clinical presentation of severe COVID-19. A growing number of serological and morphological evidence has added to this assumption, also in regard to potential treatment options. In this study, we used immunohistochemistry and histochemistry to trace NETs and their molecular markers in autopsy lung tissue from seven COVID-19 patients. Quantification of key immunomorphological features enabled comparison with non-COVID-19 diffuse alveolar damage. Our results strengthen and extend recent findings, confirming that NETs are abundantly present in seriously damaged COVID-19 lung tissue, especially in association with microthrombi of the alveolar capillaries. In addition, we provide evidence that low-density neutrophils (LDNs), which are especially prone to NETosis, contribute substantially to COVID-19-associated lung damage in general and vascular blockages in particular.

Highlights

Since the first published reports on clinical features of COVID-19 (e.g., [1]), there is cumulative evidence that critical cases could be substantially aggravated by the tissue-damaging effects of neutrophil extracellular DNA traps (NETs) [2]
acute respiratory distress syndrome (ARDS) of various etiologies had previously been shown to be accompanied with elevated serum levels of D-dimers [36], yet considerably less pronounced than in COVID-19, and cell-free DNA [35], both shown to be strongly associated with NETosis (e.g., [37])
Differences are statistically significant between COVID-19 and bacterial pneumonia for citrullinated histone H3 (citH3) + neutrophil extracellular traps (NETs), between COVID-19 and non-COVID-19 diffuse alveolar damage (DAD) for citH3+ cells with still intact nuclei, and between COVID-19 and control lungs devoid of pathology for both target variables (p < 0:05 each)

Summary

Introduction

Since the first published reports on clinical features of COVID-19 (e.g., [1]), there is cumulative evidence that critical cases could be substantially aggravated by the tissue-damaging effects of neutrophil extracellular DNA traps (NETs) [2]. Associated with a cytokine storm [3,4,5], critically ill COVID-19 patients were shown to develop conditions that had all been previously identified as closely associated with NETosis (a topic introduced by Barnes et al [6] and Mozzini and Girelli [7]) such as severe tissue injury, coagulopathy, and barrier dysfunction of the lungs [8]. Present evidence indicates that severe COVID-19 is a specific acute respiratory distress syndrome (ARDS) phenotype frequently showing diffuse alveolar damage (DAD). ARDS of various etiologies had previously been shown to be accompanied with elevated serum levels of D-dimers [36], yet considerably less pronounced than in COVID-19, and cell-free DNA [35], both shown to be strongly associated with NETosis (e.g., [37]). COVID-19 sera were found to contain abundant NETosis markers such as cell-free DNA, myeloperoxidase- (MPO-) associated DNA, and citrullinated histone H3 (citH3), together with elevated levels of the acute-phase

Methods

Results

Discussion

Conclusion