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Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype.

Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H, Sjövall H, Hansson GC - J. Exp. Med. (2012)

Bottom Line: The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM).In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties.This knowledge may provide novel therapeutic options for CF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biochemistry, University of Gothenburg, 405 30 Gothenburg, Sweden.

ABSTRACT
Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.

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The CF mucus phenotype can be normalized by apical HCO3−. (A) Total CF mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 23, 69, 92, or 115 mM apical HCO3−. (B) Remaining mucus thickness after aspiration in the presence of increasing concentrations of apical HCO3− (n = 6 for 23, 92, and apical 115; n = 3 for 69 and 115 serosal; **, P < 0.05). (C) Bright field images of CF ileal tissue with mucus secreted into 115 mM HCO3− apical buffer before and after aspiration. See Video 4 to watch the aspiration the mucus. (D) Total and remaining mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 10 or 20 mM EDTA (n = 5 in all three groups; **, P = 0.008). Data are presented as mean ± SEM.
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fig4: The CF mucus phenotype can be normalized by apical HCO3−. (A) Total CF mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 23, 69, 92, or 115 mM apical HCO3−. (B) Remaining mucus thickness after aspiration in the presence of increasing concentrations of apical HCO3− (n = 6 for 23, 92, and apical 115; n = 3 for 69 and 115 serosal; **, P < 0.05). (C) Bright field images of CF ileal tissue with mucus secreted into 115 mM HCO3− apical buffer before and after aspiration. See Video 4 to watch the aspiration the mucus. (D) Total and remaining mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 10 or 20 mM EDTA (n = 5 in all three groups; **, P = 0.008). Data are presented as mean ± SEM.

Mentions: Because HCO3− transport was required for formation of a normal mucus in WT mice, we hypothesized that increasing the concentration of NaHCO3 on the apical side of the epithelium would normalize the mucus phenotype in CF mice. The mucus on the explants was carefully removed and apical buffers with 23, 69, 92, and 115 mM NaHCO3, pH 7.4, were added. Mucus secretion was stimulated by serosal perfusion of the secretagogues CCh and PGE2. After 40 min, the thickness of the mucus was measured with paired controls (23 mM NaHCO3). The total mucus thickness was similar for all HCO3− concentrations (see Fig. 5 A). It should be pointed out that the surface of the small intestinal mucus is very loose, fluffy, and poorly held together. The surface mucus floats out to the sides and dissolves into the apical buffer. This means that the mucus is normally not observed far above the villus tips, something that may explain why no increased mucus thickness was observed with the higher HCO3− concentrations. The formed mucus was then aspirated from the paired tissues with control (23 mM) and experimental mucosal HCO3− solutions, and its thickness was measured after adding charcoal (Fig. 4 B, Remaining). The mucus remained attached in 70 mM NaHCO3, but in 92 mM NaHCO3 ∼50% of the mucus could be removed. At 115 mM NaHCO3, ∼75% of the mucus could be removed, which is similar to what is observed in WT (Fig. 4 A).


Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype.

Gustafsson JK, Ermund A, Ambort D, Johansson ME, Nilsson HE, Thorell K, Hebert H, Sjövall H, Hansson GC - J. Exp. Med. (2012)

The CF mucus phenotype can be normalized by apical HCO3−. (A) Total CF mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 23, 69, 92, or 115 mM apical HCO3−. (B) Remaining mucus thickness after aspiration in the presence of increasing concentrations of apical HCO3− (n = 6 for 23, 92, and apical 115; n = 3 for 69 and 115 serosal; **, P < 0.05). (C) Bright field images of CF ileal tissue with mucus secreted into 115 mM HCO3− apical buffer before and after aspiration. See Video 4 to watch the aspiration the mucus. (D) Total and remaining mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 10 or 20 mM EDTA (n = 5 in all three groups; **, P = 0.008). Data are presented as mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3405509&req=5

fig4: The CF mucus phenotype can be normalized by apical HCO3−. (A) Total CF mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 23, 69, 92, or 115 mM apical HCO3−. (B) Remaining mucus thickness after aspiration in the presence of increasing concentrations of apical HCO3− (n = 6 for 23, 92, and apical 115; n = 3 for 69 and 115 serosal; **, P < 0.05). (C) Bright field images of CF ileal tissue with mucus secreted into 115 mM HCO3− apical buffer before and after aspiration. See Video 4 to watch the aspiration the mucus. (D) Total and remaining mucus thickness after CCh- and PGE2-stimulated secretion into apical buffers containing 10 or 20 mM EDTA (n = 5 in all three groups; **, P = 0.008). Data are presented as mean ± SEM.
Mentions: Because HCO3− transport was required for formation of a normal mucus in WT mice, we hypothesized that increasing the concentration of NaHCO3 on the apical side of the epithelium would normalize the mucus phenotype in CF mice. The mucus on the explants was carefully removed and apical buffers with 23, 69, 92, and 115 mM NaHCO3, pH 7.4, were added. Mucus secretion was stimulated by serosal perfusion of the secretagogues CCh and PGE2. After 40 min, the thickness of the mucus was measured with paired controls (23 mM NaHCO3). The total mucus thickness was similar for all HCO3− concentrations (see Fig. 5 A). It should be pointed out that the surface of the small intestinal mucus is very loose, fluffy, and poorly held together. The surface mucus floats out to the sides and dissolves into the apical buffer. This means that the mucus is normally not observed far above the villus tips, something that may explain why no increased mucus thickness was observed with the higher HCO3− concentrations. The formed mucus was then aspirated from the paired tissues with control (23 mM) and experimental mucosal HCO3− solutions, and its thickness was measured after adding charcoal (Fig. 4 B, Remaining). The mucus remained attached in 70 mM NaHCO3, but in 92 mM NaHCO3 ∼50% of the mucus could be removed. At 115 mM NaHCO3, ∼75% of the mucus could be removed, which is similar to what is observed in WT (Fig. 4 A).

Bottom Line: The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM).In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties.This knowledge may provide novel therapeutic options for CF.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medical Biochemistry, University of Gothenburg, 405 30 Gothenburg, Sweden.

ABSTRACT
Cystic fibrosis (CF) is caused by a nonfunctional chloride and bicarbonate ion channel (CF transmembrane regulator [CFTR]), but the link to the phenomenon of stagnant mucus is not well understood. Mice lacking functional CFTR (CftrΔ508) have no lung phenotype but show similar ileal problems to humans. We show that the ileal mucosa in CF have a mucus that adhered to the epithelium, was denser, and was less penetrable than that of wild-type mice. The properties of the ileal mucus of CF mice were normalized by secretion into a high concentration sodium bicarbonate buffer (~100 mM). In addition, bicarbonate added to already formed CF mucus almost completely restored the mucus properties. This knowledge may provide novel therapeutic options for CF.

Show MeSH
Related in: MedlinePlus