Mucociliary clearance (MCC. Insoluble particles that deposit in the conducting airways (from generations 0 to 16) can become entrapped in the upper viscous mucus layer and removed from the respiratory tree in a host defence mechanism known as mucociliary clearance (Lansley, 1993). Driven by ciliary beating, inhaled particulate materials that consist of slowly dissolving or insoluble materials are most often trapped in the mucus layer and moved up to the larynx where they are swallowed into the gastro-intestinal tract (Xxxxxxx and Xxxxx, 1986). Cilia beat in coordination and adjust their frequency and phase of beating in response to neighbouring cilia, which is an important parameter for mucociliary transport (Sleigh et al., 1988). The average transport velocity in the human trachea has been estimated at 3-10 mm/min (Xxxxxx et al., 1975). Previous work showed that insoluble particles larger than 6 μm are cleared from the bronchial airways by MCC in 24 h, while relatively long retention of smaller particles in the conducting airways has been observed (Xxxxxxxx et al., 2006).
Mucociliary clearance (MCC. A current hypothesis for the pathogenesis of cystic fibrosis (CF) lung disease suggests that CFTR dysfunction leads to imbalanced ion transport, with reduced Cl-/HCO3- secretion through CFTR and accelerated Na+ absorption through the epithelial sodium channel (ENaC).33, 34 Together, these changes in ion transport may deplete the airway surface liquid (ASL) lining fluid and dehydrate luminal mucus secretions. Evidence supporting this hypothesis comes both from in vitro and animal experiments, where the critical influence of ASL hydration on mucus transport has been clearly elucidated. 35, 36 In vivo, we have shown that bronchoscopically collected secretions from CF toddlers are abnormally concentrated, as indexed by % solids measurements, and progressive dehydration is observed in older patients with more advanced disease (unpublished data). Measurements of MCC in CF patients using inhaled radiolabeled particles and gamma scintigraphy are also clearly abnormal, with marked slowing of clearance from the peripheral lung compartment, and in response to cough37, 38 the link between CFTR function and MCC was strengthened by a sub-study conducted within the GOAL Study. Twenty-one patients with the G551D mutation at four study sites had MCC measured before and after beginning treatment with ivacaftor. One month after starting therapy, MCC was markedly improved. No additional increase (or decrement) in MCC was observed after 3 months of treatment, demonstrating a sustained and reproducible response. Quantitatively, these sustained effects on MCC were similar to those previously measured acutely after inhaling hypertonic saline. Perhaps most importantly, the most impaired regions of mucus clearance in the peripheral lung were markedly improved to a degree that has not been achievable through any inhaled therapy. It is clear that adequately restoring CFTR function in the lung yields profound clinical improvements in patients with CF. As we develop new therapies aimed at improving the function of delF508-CFTR and other mutations, we unfortunately have few biomarkers that directly report on CFTR function in the lung, other than FEV1. While large changes in sweat chloride were observed with ivacaftor treatment in patients with G551D-CFTR, this biomarker has shown only small responses to treatment in patients homozygous for delF508-CFTR, despite improved lung function. Having a “pulmonary biomarker” that accurately and quantitatively reflects improved CFTR function in th...
