BACKGROUND: Neutrophil extracellular traps (NETs) have been observed in the airway in COPD, but their clinical and pathophysiological implications have not been defined.
OBJECTIVE: To determine if NETs are associated with disease severity in COPD, and how they are associated with microbiota composition and airway neutrophil function.
METHODS: NET protein complexes (DNA-Elastase and Histone-Elastase complexes), cell free DNA and neutrophil biomarkers were quantified in soluble sputum and serum from COPD patients during periods of disease stability and during exacerbations, and compared to clinical measures of disease severity and sputum microbiome. Peripheral blood and airway neutrophil function was evaluated by flow cytometry ex vivo and experimentally following stimulation of NET formation.
RESULTS: Sputum NET complexes were associated with the severity of COPD evaluated using the composite GOLD scale (p<0.0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by the COPD assessment test and higher levels of NET complexes in patients with frequent exacerbations (p=0.002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P=0.009) and dominance of Haemophilus spp operational taxonomic units. (P=0.01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with elevated sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with COPD soluble sputum.
CONCLUSION: NET formation is increased in severe COPD and is associated with more frequent exacerbations and a loss of microbiota diversity.
- Journal Article