Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated Cl- secretion.

Abstract

We evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl Ϫ 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. Salicylic acid inhibited I sc with an apparent K i of 646 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) inhibited the forskolin-induced I sc in MTEs and HBEs by 59 Ϯ 4% ( n ϭ 11) and 39 Ϯ 6% ( n ϭ 8), respectively. Nystatin was employed to selectively permeabilize the basolateral or apical membrane to determine the effect of ibuprofen on apical Cl Ϫ (I Cl ) and basolateral K ϩ (I K ) currents after stimulation by forskolin. After forskolin stimulation, ibuprofen (500 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 Ϫ channels in excised, inside-out patches from L-cells were evaluated. Ibuprofen (300 M) reduced CFTR Cl Ϫ current by 60 Ϯ 16% and this was explained by a short-lived block ( ‫ف‬ 1.2 ms) which causes an apparent reduction in single channel amplitude from 1.07 Ϯ 0.04 pA to 0.59 Ϯ 0.04 pA ( n ϭ 3). Similarly, salicylic acid (3 mM) reduced CFTR Cl Ϫ current by 50 Ϯ 8% with an apparent reduction in single channel amplitude from 1.08 Ϯ 0.03 pA to 0.48 Ϯ 0.06 pA ( n ϭ 4). Based on these results, we conclude that the NSAIDs ibuprofen and salicylic acid inhibit cAMP-mediated Cl Ϫ secretion in human colonic and airway epithelia via a direct inhibition of CFTR Cl Ϫ channels as well as basolateral membrane K ϩ 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.

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

“…Notably, ibuprofen causes voltage-dependent blockade of CFTR only when the channel is stimulated by a high concentration of cAMP. This is consistent with a previous study, which showed that high concentrations of ibuprofen inhibited the CFTR conductance, provided the channels were strongly activated by the forskolin or with the use of high concentrations of intracellular cAMP [3]. Secondly, and most importantly, clinically relevant doses of ibuprofen substantially potentiate CFTR currents in the presence of low intracellular cAMP or in undisturbed intracellular conditions, which better reflect in vivo cell physiology.…”

“…The benefit of ibuprofen treatment has been largely attributed to its antiinflammatory action. A previous study has shown that ibuprofen inhibits cAMP-activated CFTR currents in epithelial cells by an unknown mechanism [3]. This inhibitory action on the CFTR would paradoxically be anticipated to exacerbate the symptoms of CF.…”

Correction of the ΔPhe508 Cystic Fibrosis Transmembrane Conductance Regulator Trafficking Defect by the Bioavailable Compound Glafenine

“…NSAIDs such as ibuprofen, salicylic acid, and niflumic acid are open-channel blockers of CFTR (Devor and Schultz, 1998;Scott-Ward et al, 2004), which may explain the inhibition of iodide efflux by high concentrations of glafenine in the present study. Glafenine increased steady-state CFTR protein expression without affecting the level of CFTR mRNA (data not shown); however, further studies are needed to assess whether this reflects an increase in the rate of CFTR translation or its protein stability.…”

Stimulation of chloride secretion by baicalein in isolated rat distal colon

“…Similar findings have been reported in both human (24) and rabbit colon (23). In T84 cells (6) and rat colon (25), 293B selectively blocks basolateral cAMP-dependent K ϩ conductance, leading to inhibition of forskolin-dependent Cl Ϫ secretion. Recently, the cAMP-activated K v LQT1 K ϩ channel in rat colonic epithelial cells has been cloned.…”