RT Journal Article
SR Electronic
T1 Sildenafil (Viagra) corrects ΔF508-CFTR location in nasal epithelial cells from patients with cystic fibrosis
JF Thorax
JO Thorax
FD BMJ Publishing Group Ltd and British Thoracic Society
SP 55
OP 59
DO 10.1136/thx.2003.019778
VO 60
IS 1
A1 R L Dormer
A1 C M Harris
A1 Z Clark
A1 M M C Pereira
A1 I J M Doull
A1 C Norez
A1 F Becq
A1 M A McPherson
YR 2005
UL http://thorax.bmj.com/content/60/1/55.abstract
AB Background: Most patients with cystic fibrosis (CF) have a ΔF508 mutation resulting in abnormal retention of mutant gene protein (ΔF508-CFTR) within the cell. This study was undertaken to investigate ΔF508-CFTR trafficking in native cells from patients with CF with the aim of discovering pharmacological agents that can move ΔF508-CFTR to its correct location in the apical cell membrane. Method: Nasal epithelial cells were obtained by brushing from individuals with CF. CFTR location was determined using immunofluorescence and confocal imaging in untreated cells and cells treated with sildenafil. The effect of sildenafil treatment on CFTR chloride transport function was measured in CF15 cells using an iodide efflux assay. Results: In most untreated CF cells ΔF508-CFTR was mislocalised within the cell at a site close to the nucleus. Exposure of cells to sildenafil (2 hours at 37°C) resulted in recruitment of ΔF508-CFTR to the apical membrane and the appearance of chloride transport activity. Sildenafil also increased ΔF508-CFTR trafficking in cells from individuals with CF with a single copy ΔF508 (ΔF508/4016ins) or with a newly described CF trafficking mutation (R1283M). Conclusions: The findings provide proof of principle for sildenafil as a ΔF508-CFTR trafficking drug and give encouragement for future testing of sildenafil and related PDE5 inhibitors in patients with CF.