Intestinal physiology and pathology in gene-targeted mouse models of cystic fibrosis

Cystic fibrosis (CF) is a fatal genetic disorder that affects approximately 1 in 2,500 live Caucasian births. The disease can be described as a generalized exocrine disease affecting a variety of epithelial tissues, with early manifestation as meconium ileus in a significant number of neonates. Cloning of the gene causing CF was accomplished in 1989, and the protein product, cystic fibrosis transmembrane conductance regulator (CFTR), has been conclusively shown to be an adenosine 3',5'-cyclic monophosphate (cAMP)-regulated Cl- channel. Subsequently, several mouse models of CF were generated by gene-targeting approaches in an attempt to further understand this disease. The initial excitement generated by the emergence of these mouse models was somewhat tempered by the finding that none of the models developed airway disease, which is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of which there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Most importantly, the intestinal tract of the CF mouse models demonstrates the absence of cAMP-mediated Cl- transport, which is a hallmark of CF disease. Furthermore, the murine CF intestinal tract also shows an inability to secrete HCO3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as other ion transport perturbations. Besides the fundamental mechanisms of ion transport studied in the murine CF intestinal tract, these models have also been important in understanding other tissues with regard to CF. Mice heterozygous for the CFTR knockout gene have a reduced ability to secret Cl- and fluid and therefore provide further support for the CF "heterozygote advantage" hypothesis. Some CF mouse models maintain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the intestines of these mice. This review describes the CF models generated and compares the murine defects in ion transport with observed abnormalities in the human CF intestine.