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Nonsteroidal anti-inflammatory drugs upregulate function of wild-type and mutant CFTR

¹ Sunnybrook Health Sciences Centre, ² Program of Physiology and Experimental Medicine, Hospital for Sick Children, Depts of ⁴ Physiology, ⁵ Laboratory Medicine and Pathobiology, and ⁶ Anesthesia, University of Toronto, Toronto, ON, Canada, ³ The University of Hong Kong, Hong Kong, China

CORRESPONDENCE: W-Y. Lu, Research Building S104, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5 Canada, Fax: 416 4805737. E-mail: wlu{at}sten.sunnybrook.utoronto.ca

Keywords: Adenylate cyclase, chloride channel, forskolin, lung epithelium, perforated-patch recording

Received: December 13, 2007
Accepted March 13, 2008

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 (F580CFTR).

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.