| Cystic fibrosis (CF), the most common lethal genetic disease affecting Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. CF is characterized by a number of pathologies including pancreatic enzyme insufficiency, meconium ileus, distal intestinal obstructive disease, bone abnormalities, and airway mucociliary clearance failure leading to repeated bouts of lung infections. In addition to its role as a cAMP stimulated anion channel, CFTR has been shown to regulate other ion transport pathways. It is the goal of this research to elucidate the role that CFTR plays in the pathogenesis of CF and the regulation of other ion transport processes. Similar to findings in CF patients, CF mice have severe intestinal disease, reduced growth, and abnormal dentition. However, while alterations in tooth mineral composition were found, no differences in bone mineralization were detected in CF mice. This indicates that it is likely that human CF bone disease is not a direct result of loss of CFTR but rather is secondary to other disease and treatment factors. In the intestine, we found that NHE3 is the principal Na+/H+ exchanger involved in electroneutral Na+ absorption. In addition, we conclude that pharmacological blockade of cAMP-stimulated Cl− secretion prevents a portion of the cAMP-induced inhibition of Na + absorption. Furthermore, intestinal Na+ absorption was abolished in both control and CF jejuna under all experimental conditions that resulted in reduced epithelial cell volume. Together, these two findings suggest that activation of CFTR results in cell shrinkage that is required for complete inhibition of intestinal Na+/H+ exchange by cAMP. In summary, these experiments have resulted in: (1) elimination of the CF mouse as a model for human CF bone disease; (2) demonstration of a dominant role for NHE3 in electroneutral Na+ absorption across the murine small intestine; and (3) proposition of a novel model for the mechanism of CFTR-dependent regulation of electroneutral Na+ absorption in small intestinal epithelium. |
