Partial correction of defective Cl- secretion in cystic fibrosis epithelial cells by an analog of squalamine

Defective cystic fibrosis (CF) transmembrane conductance regulator (CFTR)-m ediated Cl- transport across the apical membrane of airway epithelial cells is implicated in the pathophysiology of CF lungs. A strategy to compensate for this loss is to augment Cl- transport through alternative pathways. We report here that partial correction of this defect could be attained throu gh the incorporation of artificial anion channels into the CF cells. Introd uction of GL-172, a synthetic analog of squalamine, into CFT1 cells increas ed cell membrane halide permeability. Furthermore, when a Cl- gradient was generated across polarized monolayers of primary human airway or Fischer ra t thyroid cells in an Ussing chamber, addition of GL-172 caused an increase in the equivalent short-circuit current. The magnitude of this change in s hort-circuit current was similar to 30% of that attained when CFTR was maxi mally stimulated with cAMP agonists. Patch-clamp studies showed that additi on of GL-172 to CFT1 cells also increased whole cell Cl- currents. These cu rrents displayed a linear current-voltage relationship and no time dependen ce. Additionally, administration of GL-172 to the nasal epithelium of trans genic CF mice induced a hyperpolarization response to perfusion with a low- Cl- solution, indicating restoration of Cl- secretion. Together, these resu lts demonstrate that in CF airway epithelial cells, administration of GL-17 2 is capable of partially correcting the defective Cl- secretion.