Impaired mucus detachment disrupts mucociliary transport in a piglet model of cystic fibrosis

Abstract

Lung disease in people with cystic fibrosis (CF) is initiated by defective host defense that predisposes airways to bacterial infection. People with advanced CF exhibit deficits in mucociliary transport (MCT), a process that traps and propels bacteria out of lungs, but whether this occurs first or is secondary to airway remodeling has been unclear. To assess MCT, we tracked movement of radiodense microdisks in airways of newborn CF piglets. Cholinergic stimulation, which elicits mucus secretion, caused microdisks to become stuck. Impaired MCT was not due to periciliary liquid depletion; rather, CF submucosal glands secreted mucus strands that remained tethered to gland ducts and hindered MCT. Inhibiting anion secretion in non-CF airways replicated CF abnormalities. These findings identify impaired MCT as a primary defect, link CFTR loss in submucosal glands to failure of mucus detachment from glands, and suggest that submucosal glands and tethered mucus may be targets for early CF treatment.

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

“…An advantage is that we used a porcine model of CF that develops the characteristic features of CF lung disease (29,30). To avoid the effects of longterm infection and inflammation, including potential epigenetic changes in epithelial cells, we generated airway epithelia from newborn animals, which we previously showed exhibit airway host defense defects (30,31,33). We found comparable results in CFTR −/− and CFTR ΔF508/ΔF508 epithelia.…”

“…Epithelia with mixed cell types showed intermediate levels of bacterial killing, consistent with the rates of HCO 3 − secretion and ASL pH. CF mucus has altered properties that impair mucociliary transport (31). Recent studies showed that CF ASL has an increased viscosity due to a reduced ASL pH (32,35).…”

“…A limitation of this study is that loss of CFTR may influence the function of other cell types and structures, including submucosal glands (31,55), airway smooth muscle (56), cartilage (57,58), and myeloid-derived cells (59). Impairment of their function might also contribute to the pathogenesis of CF airway disease.…”

“…The * indicates the difference from epithelia with 100% WT cells by repeated measures ANOVA, P < 0.05. epithelium are WT or overexpress CFTR, Cl − secretion rises to the level of WT epithelia (10)(11)(12)(13)(14). However, knowledge that CFTR conducts HCO 3 − (48), that HCO 3 − is the major pH buffer of ASL (49), and that HCO 3 − secretion plays a key role in airway host defense (31)(32)(33)(34)(35)50) led us to test the relationship between CFTR expression and HCO 3 − secretion. We found that, unlike Cl − secretion, HCO 3 − secretion was directly proportional to CFTR expression.…”

“…By studying newborn CF piglets, we identified at least two airway host defense defects (2). Mucociliary transport is impaired by mucus with abnormal biophysical properties (31,32), and the activity of airway surface liquid (ASL) antimicrobials and synergism between antimicrobials are impaired (33,34). CF ASL has an abnormally low pH, which reduces the activity of ASL antimicrobials and increases the viscosity of ASL.…”