Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation

Abstract

Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

Biofilm mechanics: Implications in infection and survival

“…This eDNA is largely of human origin [ 54 ], and is presumably released during inflammatory cell death or NETosis. NETosis (neutrophil extracellular traps) is the process whereby neutrophils extrude their cellular DNA content, coated with antimicrobial enzymes and proteins, that trap and kills microorganisms [ 55 ]. The presence of eDNA significantly increases CF sputum viscoelasticity, and subsequently increased eDNA concentrations is associated with poorer lung function, presumably because the mucus is more difficult to clear [ [52] , [53] , [54] , 56 ].…”

The Natural Polypeptides as Significant Elastase Inhibitors

“…HNE also localizes to Neutrophil extracellular traps (NETs) through its high DNA affinity, an unusual property for serine proteases. Studies have established that NETs are associated with increased lung injury and mucus clogging in cystic fibrosis (Thomas et al, 2014;Khan et al, 2019). A wide variety of studies have highlighted the proteolytic activity of elastase in causing structural changes, such as higher mean linear intercept and alveolar enlargement both in mice and in rats.…”

Airway Inflammation and Host Responses in the Era of CFTR Modulators

“…Loss of the ASL barrier leaves mucosal surfaces exposed and more susceptible to the damaging effects of chronic infection and toxic inflammatory products. Acidification of the ASL through reduced CFTR-mediated bicarbonate transport [ 33 ] impairs phagocyte function [ 40 ] and ciliary beat frequency [ 41 ], adding to the burden of uncleared pathogens and mucoinflammatory products within the airways. Furthermore, mucus viscosity is altered by the abundance of free neutrophilic actin and long-stranded DNA [ 42 ], as well as increased IL-1α and IL-1β mucin stimulation (MUC5B and MUC5AC) [ 43 ], making it more difficult to clear from the airways.…”