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
Published August 24, 2009
Citation Information: J Clin Invest. 2009;119(9):2613-2622. https://doi.org/10.1172/JCI38662.
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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 11

Possible mechanism for HCO3–-dependent expansion and solubilization of granules of condensed mucins.

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Possible mechanism for HCO3–-dependent expansion and solubilization of g...
Intracellularly, mucins are condensed in granules by high concentrations of Ca2+ and H+, which shield the repulsive forces of the high density of negative charges on the anionic sites of mucin glycoproteins. As granules are secreted, released mucin must be accompanied by rapid dissociation of Ca2+ and H+ from the mucin to unshield the fixed negative sites. The repulsive intramolecular electrostatic forces from exposed anionic sites then expand the mucin molecule extensively. Rapid expansion of the mucin molecule may be important to forming the network of macromolecules that become “normal mucus.” Beyond this simplistic effect at the “moment of birth,” however, HCO3– may be critically involved in other, more complicated processes for disaggregation and unraveling of mucin polypeptide domains and/or further interactions with proteins and other moieties. Thus, the presence of a competing anion such as HCO3– in the extracellular media that efficiently sequesters these mucin-bound cations may optimize mucin expansion and intermolecular disaggregation, while its absence may bear heavily on the abnormal forms of aggregated mucus found in CF.