The CFTR-mediated protein secretion defect: pharmacological correction

The cystic fibrosis transmembrane conductance regulator (CFTR) mediates sec retion of mucins and serous proteins. The aim was to correct pharmacologica lly the CFTR defect in protein secretion in airway gland cells and so to co rrect the viscous mucous secretions in cystic fibrosis (CF) airways and lun gs. The strategies tested included direct activation of CFTR, bypass of CFT R-mediated protein secretion and movement of the mutated form of CFTR (Delt aF(508)-CFTR) to the cell membrane. Compounds related to 3-isobutyl-1-maeth yl-xanthine (IBMX), including a selective type-IV phosphodiesterase inhibit or and the adenosine receptor antagonists 8-cyclopentyltheophylline (CPT) a nd 8-cyclopentyl-1,3-dipropylxanthine (CPX), corrected the defective beta - adrenergic stimulation of mucin secretion in CFTR antibody-inhibited subman dibular gland cells. CPT also corrected lactoferrin secretion in DeltaF(508 )/DeltaF(508)-CFTR nasal gland cells. The data suggest that correction of C FTR protein secretion activity is not mediated by excessive increase in cyc lic AMP, involves direct interaction with CFTR but does not require increas e in CFTR Cl- channel activity. Regulated glycoprotein secretion was charac terised in the airway gland cell line Calu-3 to investigate whether a CFTR bypass is present. Studies of DeltaF(508)-CFTR trafficking using confocal i maging showed that some DeltaF(508)-CFTR colocalised with the apical membra ne protein CD59; however a large amount was mislocalised within the cell. T he results showing pharmacological correction of the defective CFTR-mediate d protein secretion afford promise for the development of a rational drug t herapy for CF patients.