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

https://doi.org/10.1016/j.jaci.2017.04.022Get rights and content
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Background

Neutrophil 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.

Objective

We 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.

Methods

NET 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.

Results

Sputum 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.

Conclusion

NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

Key words

Neutrophils
phagocytosis
chronic obstructive pulmonary disease
Haemophilus species
exacerbations

Abbreviations used

CAT
COPD Assessment Test
cfDNA
Cell-free DNA
COPD
Chronic obstructive pulmonary disease
EN-RAGE
Ligand for the receptor for advanced glycation end products
GOLD
Global Initiative for Obstructive Lung Disease
ICS
Inhaled corticosteroid
MPO
Myeloperoxidase
MRC
Medical Research Council
NET
Neutrophil extracellular trap
OTU
Operational taxonomic unit
PMA
Phorbol 12-myristate 13-acetate
SWDI
Shannon-Wiener species diversity index

Cited by (0)

Supported by the Chief Scientist Office, Scotland (grant no. ETM/262). J.D.C. acknowledges fellowship support from the Wellcome Trust. S.E.M. is an employee of the Wellcome Trust.

Disclosure of potential conflict of interest: O. Sibila has received grants from AstraZeneca and Menarini. J. S. Elborn has received a grant from Novartis. S. Schembri has received a grant from GlaxoSmithKline. C. N. A. Palmer has received a grant from AstraZeneca. J. D. Chalmers has received grants from AstraZeneca and Boehringer Ingelheim. The rest of the authors declare that they have no relevant conflicts of interest.