Mucociliary Transport in Healthy and Cystic Fibrosis Pig Airways

Abstract

Cystic fibrosis (CF) lung disease is the major cause of morbidity and mortality in people with CF. Abnormal mucociliary transport has been the leading hypothesis for the underlying pathogenesis of CF airway disease. However, this has been difficult to investigate at very early time points. A porcine CF model, which recapitulates many features of CF disease in humans, enables studies to be performed in non-CF and CF pigs on the day that they are born. In newborn CF pigs, we found that under basal conditions, mucociliary transport rates in non-CF and CF pigs are similar. However, after cholinergic stimulation, which stimulates submucosal gland secretion, particles become stuck in the CF airways owing to a failure of mucus strands to release from submucosal glands. In this review, we summarize these recent discoveries and also discuss the morphology, composition, and function of mucins in the porcine lung.

Keywords: cystic fibrosis; mucociliary transport; mucus; submucosal gland.

Figure 1.

Three-dimensional reconstructed images created using X-ray computed tomography reveal in vivo mucociliary transport in newborn pigs. (A) Individual tantalum microdisks (diameter, ∼350 μm) travel up the airways in 3 minutes. Individual microdisks are represented by different colors spheres (enlarged for visualization). Microdisk trajectories are connected by lines. Microdisks move with substantially heterogeneous speeds at different time points. (B) Microdisks are immobile, or fail to move, a greater percentage of the time in methacholine-treated newborn cystic fibrosis (CF) pig airways. *P < 0.05. Data are from Reference .

Figure 2.

Staining of airway mucus and epithelial cells. Mucus strands, composed with MUC5B (stained red with wheat germ agglutinin [WGA]), emerge from submucosal gland duct openings (large arrows) and are partially coated with MUC5AC threads (small arrows) (stained green with jacalin [JAC]) from goblet cells. 4′,6-Diamidino-2-phenylindole (DAPI) nuclei = gray. Scale bar = 120 μm. Additional images comparing non–cystic fibrosis and cystic fibrosis can be found in Reference .

Figure 3.

Mucus secretion and transport in the airways. (A) Model of mucus secretion in pig large airways. Within submucosal glands (SMGs), MUC5B-predominant mucus (red lines) is secreted from mucous cells; serous cells express cystic fibrosis transmembrane conductance regulator (CFTR), determine pH, volume, and ionic composition of submucosal gland lumen and mucus. Mucus strands are coated with MUC5AC threads (green lines) or sheets. MUC5AC sheets and threads are predominantly secreted by surface goblet cells. (B) Model of mucus secretion in large and small airways.