Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator-dependent bicarbonate secretion.
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.
Garcia
Mary Abigail S
MA
Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California School of Medicine, San Diego, California 92093-0831, USA.
Yang
Ning
N
Quinton
Paul M
PM
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D002034:Bumetanide / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D017136:Ion Transport; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D008954:Models, Biological; D009093:Mucus / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027982:Sodium-Bicarbonate Symporters / Q000037:antagonists & inhibitors
D001639:Bicarbonates; C505032:CFTR protein, human; C498899:Slc4a4 protein, mouse; D049994:Sodium Potassium Chloride Symporter Inhibitors; D027982:Sodium-Bicarbonate Symporters; D002034:Bumetanide; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012701:Serotonin; D015232:Dinoprostone; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid