Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion
Mary Abigail S. Garcia, Ning Yang, Paul M. Quinton
Mary Abigail S. Garcia, Ning Yang, Paul M. Quinton
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Research Article

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 (HCO3–) transport and that HCO3– is critical for normal mucus formation. We therefore investigated the role of HCO3– in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO3– were similar. However, in the absence of HCO3–, mucus release stimulated by either PGE2 or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO3–. Inhibition of HCO3– and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO3– nor inhibition of HCO3– transport affected fluid secretion rates, indicating that the effect of HCO3– 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 PGE2 or 5-HT in the presence or absence of HCO3–. These data suggest that normal mucus release requires concurrent HCO3– secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO3– transport.

Authors

Mary Abigail S. Garcia, Ning Yang, Paul M. Quinton

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Figure 10

Conceptual arrangement of mucus cells and enterocytes with components of Cl– and HCO3– secretion and corresponding inhibitors.

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Conceptual arrangement of mucus cells and enterocytes with components of...
In general, HCO3– is thought to be taken up across the basolateral membrane mainly via NBC, which is inhibited by DIDS. HCO3– exits the cell across the apical membrane, possibly via a CFTR-dependent Cl–/HCO3– exchanger (also DIDS sensitive) or directly through the CFTR anion conductive channel that is inhibited by GlyH-101. Fluid secretion is dependent upon the uptake of Cl– via the NKCC in the basolateral membrane, which is inhibited by bumetanide and on CFTR (or other Cl– channels not shown) in the apical membrane. Thus, DIDS should block HCO3– secretion, and bumetanide should block fluid secretion. GlyH-101 is expected to inhibit both CFTR-dependent fluid and HCO3– secretion either directly by blocking CFTR conductance or indirectly by inhibiting a CFTR-dependent Cl–/HCO3– exchanger (65). The diagram intentionally suggests close proximity of HCO3–-secreting enterocytes, with mucus-secreting goblet cells and possibly enterocytes as a means of maintaining ample HCO3– in the immediate environment of secreted mucin granules. In CF, defunct CFTR would starve the environment of HCO3–.