Expression of delta F508 cystic fibrosis transmembrane conductance regulator protein and related chloride transport properties in the gallbladder epithelium from cystic fibrosis patients

Cystic fibrosis transmembrane conductance regulator (CFTR), the cystic fibr osis (CF) gene product, functions as an adenosine 3',5'-cyclic monophosphat e (cAMP)-regulated chloride channel in the epical membrane of biliary epith elial cells, including gallbladder epithelial cells, It has been shown that Delta F508, the most common CF mutation, impedes CFTR trafficking to the a pical surface of epithelial cells. To elucidate the mechanisms of CF biliar y disease, we examined structural features, CFTR expression, and chloride t ransport properties in gallbladder epithelial cells from nine Delta F508 ho mozygous liver transplant recipients. Three CF patients had microgallbladde rs, characterized by severe histological abnormalities. Microgallbladder ep ithelial cells displayed aberrant immunolocalization of CFTR and of other n ormally apical proteins in the lateral domain of their plasma membrane and in their cytoplasm. This pattern was mimicked by chronic cholecystitis in n on-CF patients, In the 6 remaining CF patients, CFTR was predominantly apic al in the gallbladder epithelium, consistent with the detection of a fully glycosylated form by Western blot. In CF as compared with non-CF gallbladde r epithelial cells in primary culture, chloride efflux was lower in respons e to cAMP and tended to be higher in response to exogenous adenosine 5'-tri phosphate (ATP), The CF cells exhibited a residual cAMP-dependent chloride secretion that was inversely correlated with ATP-induced chloride secretion , and almost completely blunted in the cells derived from microgallbladders . Our results suggest that epithelial structural alterations aggravate Delt a F508 CFTR mislocalization in the gallbladder epithelium. The associated d ecrease in residual cAMP-dependent chloride secretion may contribute to bil iary damage despite the up-regulation of alternative chloride transport pat hways.