Nonsteroidal anti-inflammatory drugs upregulate function of wild-type and mutant CFTR.
Small-scale clinical trials show that treatment of cystic fibrosis (CF) patients with ibuprofen, a nonsteroidal anti-inflammatory drug, improves the symptoms of CF and slows down the decline of lung function. Paradoxically, ibuprofen inhibits ligand-stimulated CF transmembrance conductance regulator (CFTR) activity. The aim of the present study was to investigate the effects of ibuprofen on CFTR function under different conditions. Patch-clamp recordings were performed in two lines of human airway epithelial cells: IB3-8-3-7 cells, which express wild-type CFTR; and IB3-1 cells, which express the variant CFTR with deletion of phenylalanine 580 (DeltaF580CFTR). Addition of ibuprofen to the extracellular solution caused a rapid inhibition of CFTR activity in IB3-8-3-7 cells in the presence of a high intracellular concentration of cAMP, whereas ibuprofen enhanced the CFTR conductance at low levels of cAMP. Introducing ibuprofen into the interior of cells occluded the enhancing effect of ibuprofen. Notably, the variant CFTR-mediated conductance was detected in IB3-1 cells treated with myoinositol and was enhanced by ibuprofen at endogenous levels of cAMP. In summary, nonsteroidal anti-inflammatory drugs increase the function of both wild-type cystic fibrosis transmembrane conductance regulator and the phenylalanine 580 deletion in cultured human airway epithelial cells at endogenous levels of cAMP.
Li
J
J
Research Building S104, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON M4N3M5, Canada.
Xiang
Y-Y
YY
Ye
L
L
Tsui
L-C
LC
Macdonald
J F
JF
Hu
J
J
Lu
W-Y
WY
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D018408:Patch-Clamp Techniques; D018079:Receptors, GABA / Q000378:metabolism; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018079:Receptors, GABA; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D007052:Ibuprofen