Transcriptional Insights of Oxidative Stress and Extracellular Traps in Lung Tissues of Fatal COVID-19 Cases

Neutrophil extracellular traps (NETs) and oxidative stress are considered to be beneficial in the innate immune defense against pathogens. However, defective clearance of NETs in the lung of acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients could lead to severe respiratory syndrome infection, the so-called coronavirus disease 2019 (COVID-19). To elucidate the pathways that are related to NETs within the pathophysiology of COVID-19, we utilized RNA sequencing (RNA-seq) as well as immunofluorescence and immunohistochemistry methods. RNA-seq analysis provided evidence for increased oxidative stress and the activation of viral-related signaling pathways in post-mortem lungs of COVID-19 patients compared to control donors. Moreover, an excess of neutrophil infiltration and NET formation were detected in the patients' lungs, where the extracellular DNA was oxidized and co-localized with neutrophil granule protein myeloperoxidase (MPO). Interestingly, staining of the lipid peroxidation marker 4-hydroxynonenal (4-HNE) depicted high colocalization with NETs and was correlated with the neutrophil infiltration of the lung tissues, suggesting that it could serve as a suitable marker for the identification of NETs and the severity of the disease. Moreover, local inhalation therapy to reduce the excess lipid oxidation and NETs in the lungs of severely infected patients might be useful to ameliorate their clinical conditions.

Automated summary

Neutrophil extracellular traps (NETs) and oxidative stress play important roles in the immune defense against pathogens. However, impaired clearance of NETs in the lungs of COVID-19 patients may contribute to severe respiratory syndrome infection. Through RNA sequencing (RNA-seq) and immunofluorescence and immunohistochemistry methods, the study identified increased oxidative stress and viral-related signaling pathways in COVID-19 patients' lungs. Excess neutrophil infiltration and NET formation, with oxidized extracellular DNA co-localizing with myeloperoxidase (MPO), were observed. The lipid peroxidation marker 4-hydroxynonenal (4-HNE) showed high colocalization with NETs and correlated with lung neutrophil infiltration, suggesting its potential as a marker for identifying NETs and disease severity. Local inhalation therapy to reduce lipid oxidation and NETs may benefit severely infected patients.