Ibuprofen Inhibits Cystic Fibrosis Transmembrane Conductance

We evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl 2 secretion (I sc ) in both colonic and airway epithelia. In T84 cells, ibuprofen inhibited the forskolin-dependent I sc in a concentration-dependent manner, having an apparent K i of 142 m M. Salicylic acid inhibited I sc with an apparent K i of 646 m M. We determined whether ibuprofen would also inhibit the forskolin-stimulated I sc in primary cultures of mouse trachea epithelia (MTE) and human bronchial epithelia (HBE). Similar to our results in T84 cells, ibuprofen (500 m M) inhibited the forskolin-induced I sc in MTEs and HBEs by 59 6 4% ( n 5 11) and 39 6 6% ( n 5 8), respectively. Nystatin was employed to selectively permeabilize the basolateral or apical membrane to determine the effect of ibuprofen on apical Cl 2 (I Cl ) and basolateral K 1 (I K ) currents after stimulation by forskolin. After forskolin stimulation, ibuprofen (500 m M) reduced both the I Cl and I K ; reducing I Cl and I K by 60 and 15%, respectively. To determine whether this inhibition of I Cl was due to the inhibition of CFTR, the effects of ibuprofen and salicylic acid on CFTR Cl 2 channels in excised, inside-out patches from L-cells were evaluated. Ibuprofen (300 m M) reduced CFTR Cl 2 current by 60 6 16% and this was explained by a short-lived block ( z 1.2 ms) which causes an apparent reduction in single channel amplitude from 1.07 6 0.04 pA to 0.59 6 0.04 pA ( n 5 3). Similarly, salicylic acid (3 mM) reduced CFTR Cl 2 current by 50 6 8% with an apparent reduction in single channel amplitude from 1.08 6 0.03 pA to 0.48 6 0.06 pA ( n 5 4). Based on these results, we conclude that the NSAIDs ibuprofen and salicylic acid inhibit cAMP-mediated Cl 2 secretion in human colonic and airway epithelia via a direct inhibition of CFTR Cl 2 channels as well as basolateral membrane K 1 channels. This may reduce their efficacy in conjunction with other therapeutic strategies designed to increase CFTR expression and/or function in secretory epithelia. ( J. Clin. Invest. 1998. 102:679–687.)