INTESTINAL PHYSIOLOGY AND PATHOLOGY IN GENE-TARGETED MOUSE MODELS OF CYSTIC-FIBROSIS

Cystic fibrosis (CF) is a fatal genetic disorder that affects approxim ately 1 in 2,500 live Caucasian births. The disease can be described a s a generalized exocrine disease affecting a variety of epithelial tis sues, with early manifestation as meconium ileus in a significant numb er of neonates. Cloning of the gene causing CF was accomplished in 198 9, 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, seve ral 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, whic h is currently responsible for most of the morbidity and mortality in the human CF population. However, the various CF mouse models, of whic h there are now 10, are remarkably similar to their human counterparts with respect to intestinal pathophysiology. Nest importantly, the int estinal 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 HC O3-, defective cAMP regulation of electroneutral NaCl absorption, and elevated electrogenic Na+ transport in the distal colon, as well as ot her 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 t o CF. Mice heterozygous for the CFTR knockout gene have a reduced abil ity to secrete Cl- and fluid and therefore provide further support for the CF ''heterozygote advantage'' hypothesis. Some CF mouse models ma intain a limited ability to secrete Cl-, which may be due to accessory genes that are hypothesized to ameliorate disease severity in the int estines of these mice. This review describes the CF models generated a nd compares the murine defects in ion transport with observed abnormal ities in the human CF intestine.