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.

TMEM16A chloride channel does not drive mucus production

“…Moreover, it was shown that inhibition of anion secretion in non-CF airways replicates these CF abnormalities (Hoegger et al, 2014). More recently, based on data obtained in newborn CFTR knockout piglets, it was proposed that MUC5AC (produced by goblet cells) anchors the mucus bundles, mostly composed by MUC5B (produced by submucosal glands), thus being the key controller of mucus transport (Ermund et al, 2017; Xie et al, 2018). Furthermore, the number of MUC5AC-mediated anchorage points in CF mucus is much higher than in non-CF mucus, and without sufficient HCO 3 − , the mucus cannot detach from its goblet cell anchor, initiating CF lung disease (Ermund et al, 2017; Xie et al, 2018).…”

Factoring in the Complexity of the Cystic Fibrosis Lung to Understand Aspergillus fumigatus and Pseudomonas aeruginosa Interactions

“…Submucosal glands produce mucus strands that detach from the epithelium and comprise the mucus layer. Lack of mucus strand detachment thus contributes to abnormal mucus composition, impaired mucociliary transport and the obstruction of small airways [ 42 , 43 ].…”

Chair’s Summary: Secreted Mucins in Lung Diseases

“…David Stoltz described studies of newborn pigs with cystic fibrosis showing defects in mucociliary transport owing to the formation of mucus strands that fail to detach after cholinergic stimulation of submucosal gland secretion (pp. S171-S176) (13).…”