Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease

Abstract

BackgroundNeutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined.ObjectiveWe sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function.MethodsNET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation.ResultsSputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased 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 soluble sputum from patients with COPD.ConclusionNET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

NETs in pneumonia: is just enough the right amount?

“…An additional consideration is how NETs may interact with other parts of the immune system and how this may have a bearing on disease processes. This is further underlined by the finding that levels of NETs are inversely correlated to lung function in cystic fibrosis (CF) [11], and disease severity in chronic obstructive pulmonary disease [12]. A major caveat to all of these studies is that they don't differentiate increased NET production from decreased NET clearance, which may be a crucial missing piece in the puzzle.…”

The contribution of respiratory microbiome analysis to a treatable traits model of care

“…This finding is supported by studies showing that sputum microbiome diversity in stable patients with severe asthma is inversely correlated with sputum neutrophil levels, but not with the levels of eosinophils . Similarly, sputum microbiome diversity of patients with COPD has been shown to be inversely correlated with sputum neutrophilic markers . Evidence of such an effect can also be found in studies of CF and non‐CF bronchiectasis .…”

“…20,63 Similarly, sputum microbiome diversity of patients with COPD has been shown to be inversely correlated with sputum neutrophilic markers. 64 Evidence of such an effect can also be found in studies of CF 65 and non-CF bronchiectasis. 54 A mechanism that might explain this relationship is the selective pressure exerted on the bacterial community in regions of the lower airways by airway neutrophils, where antimicrobial defence mechanisms such as neutrophil extracellular traps select for more neutrophil-resistant bacteria.…”

Advancing the management of obstructive airways diseases through translational research

“…The airway microbiome is a research field where the need for translational research is evident: clinical studies have shown that the airway microbiome is altered in asthma and COPD, changes during exacerbations, and is affected by both antibiotic and anti‐inflammatory treatment . The microbiome is furthermore linked to patterns of airway inflammation, but the causality remains unclear. Experimental studies will be key in uncovering the effect of manipulating the airway microbiome, as well as the role of the interaction with the immune system …”