Neutrophil extracellular traps are associated with airways inflammation and increased severity of lung disease in cystic fibrosis

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Background: Cystic fibrosis (CF) is characterised by inflammatory lung disease and large numbers of airways neutrophils. In health, neutrophils undergo apoptosis and removal from the airway. Since CF neutrophils are known to engage in apoptosis less efficiently, we wanted to assess whether alternative forms of neutrophil clearance such as NETosis were prominent in the CF airway. Methods: Sputum and blood were collected from 45 CF and 15 healthy control (HC) participants. Neutrophil morphology and biochemical properties were assessed in CF and HC sputum. Neutrophil extracellular traps (NETs) were measured by a novel histone-calprotectin ELISA. NET levels were compared with established measurements of airway inflammation. CF participants were followed up for 1 year and the number of exacerbations recorded. Neutrophil and macrophage co-culture experiments were undertaken with cells from CF and HC. Results: Neutrophil numbers were significantly higher in CF and associated with abnormal morphology. Several inflammatory mediators were elevated in CF sputum, as was cell-free DNA. This was highly correlated with sputum calprotectin, a known NET-associated protein. Using a histone-calprotectin NET ELISA, we demonstrated higher levels of NETs in the CF airway. CF participants treated with DNase had fewer sputum NETs, and in neutrophil/macrophage co-culture experiments, DNase effectively attenuated the pro-inflammatory potential of NETs, suggesting a previously unrecognised anti-inflammatory role for this treatment. Conclusions: NETs in the CF airway are associated with increased levels of inflammatory mediators and more severe lung disease. NET effects on macrophages can be blocked by DNase, suggesting an anti-inflammatory role for this treatment in CF.

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