Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion

Abstract

The mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO 3 -) transport and that HCO 3 -is critical for normal mucus formation. We therefore investigated the role of HCO 3 -in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO 3 -were similar. However, in the absence of HCO 3 -, mucus release stimulated by either PGE 2 or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO 3 -. Inhibition of HCO 3 -and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO 3 -nor inhibition of HCO 3 -transport affected fluid secretion rates, indicating that the effect of HCO 3 -removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE 2 or 5-HT in the presence or absence of HCO 3 -. These data suggest that normal mucus release requires concurrent HCO 3 -secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO 3 -transport.

Parathyroid hormone (PTH) rapidly enhances CFTR-mediated HCO3− secretion in intestinal epithelium-like Caco-2 monolayer: a novel ion regulatory action of PTH

“…The exact physiological significance of the PTH-stimulated HCO 3 Ϫ secretion in vivo remains elusive, but it might contribute to intestinal mucous and fluid secretion, optimization of extracellular pH in the brush border microclimate, and/or maintenance of the intracellular pH and volume (13,22). Our preliminary study in the in situ ligated loops of various rat intestinal segments revealed a significant dilution of sodium ferrocyanide, a nonabsorbable marker of water transport, only in the ileum within 20 min after a single intravenous PTH administration (S. Laohapitakworn and N. Charoenphandhu, unpublished observations), suggesting that PTH induced fluid secretion in rat ileum.…”

Gel-forming mucins form distinct morphologic structures in airways

“…Whether the abnormalities in CF mucus result from reduced liquid volume, decreased HCO 3 − concentration, abnormally acidic pH, or some combination of these is uncertain (21). A reduced HCO 3 − concentration was reported to contribute to intestinal mucin abnormalities in CF mice (36)(37)(38). In CF pigs, a decreased pH, rather than a decreased HCO 3 − concentration, increased airway surface liquid viscosity (29).…”

Characterization of CFTR High Expresser cells in the intestine

“…We speculate that the role of CHE cells is to liquefy lumen content and thus assist in mucus clearance. The proximal jejunum, where CHE cells are most abundant, possesses a particularly low luminal pH that can promote accumulation of firm adherent mucus on epithelial surfaces and intervillus spaces (18,24,28). Indeed, CFTR abundance in CHE cells increases as the cells migrate toward the villus tip, suggesting that the most robust secretion emanates from CHE cells in the villus region.…”