Non-steroidal anti-inflammatory drugs up-regulate function of wild-type and mutant CFTR

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

^* To whom correspondence should be addressed. E-mail: wlu{at}sten.sunnybrook.utoronto.ca;.

	Abstract

Small-scale clinical trials show that treatment of cystic fibrosis (CF) patients with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), improves the symptoms of CF and slows down the decline of lung function. Paradoxically, ibuprofen inhibits ligand-stimulated CFTR activity. The aim of this 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 cell that generates wild-type CFTR and IB3-1 cell that expresses the mutant CFTR with deletion of F580 (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 high intracellular concentration 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 mutant-CFTR-mediated conductance was detected in IB3-1 cells treated with myoinositol, which was enhanced by ibuprofen at endogenous levels of cAMP.

In summary, NSAIDs increase the function of both wild-type CFTR and F580CFTR in cultured human airway epithelial cells at endogenous levels of cAMP.