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Ibuprofen Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Cl- Secretion

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Ibuprofen Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-Mediated Cl- Secretion Ibuprofen inhibits cystic fibrosis transmembrane conductance regulator-mediated Cl- secretion. D C Devor, B D Schultz J Clin Invest. 1998;102(4):679-687. https://doi.org/10.1172/JCI2614. Research Article We evaluated the acute effects of ibuprofen and salicylic acid on cAMP-mediated Cl- secretion (Isc) in both colonic and airway epithelia. In T84 cells, ibuprofen inhibited the forskolin-dependent Isc in a concentration-dependent manner, having an apparent Ki of 142 microM. Salicylic acid inhibited Isc with an apparent Ki of 646 microM. We determined whether ibuprofen would also inhibit the forskolin-stimulated Isc in primary cultures of mouse trachea epithelia (MTE) and human bronchial epithelia (HBE). Similar to our results in T84 cells, ibuprofen (500 microM) inhibited the forskolin-induced Isc in MTEs and HBEs by 59+/-4% (n = 11) and 39+/-6% (n = 8), respectively. Nystatin was employed to selectively permeabilize the basolateral or apical membrane to determine the effect of ibuprofen on apical Cl- (ICl) and basolateral K+ (IK) currents after stimulation by forskolin. After forskolin stimulation, ibuprofen (500 microM) reduced both the ICl and IK; reducing ICl and IK by 60 and 15%, respectively. To determine whether this inhibition of ICl was due to the inhibition of CFTR, the effects of ibuprofen and salicylic acid on CFTR Cl- channels in excised, inside-out patches from L-cells were evaluated. Ibuprofen (300 microM) reduced CFTR Cl- current by 60+/-16% and this was explained by a short-lived block (approximately 1.2 ms) which causes an apparent reduction in single channel amplitude from 1.07+/-0.04 pA to […] Find the latest version: https://jci.me/2614/pdf Ibuprofen Inhibits Cystic Fibrosis Transmembrane Conductance Regulator–mediated Cl2 Secretion Daniel C. Devor and Bruce D. Schultz Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 Abstract Introduction We evaluated the acute effects of ibuprofen and salicylic Cystic fibrosis (CF)1 is characterized by persistent Pseudomo- 2 acid on cAMP-mediated Cl secretion (Isc) in both colonic nas aeruginosa colonization of the conducting airways leading and airway epithelia. In T84 cells, ibuprofen inhibited the to the migration of inflammatory cells, including polymorpho- forskolin-dependent Isc in a concentration-dependent man- nuclear leukocytes (PMNs), into the airways of CF patients. It ner, having an apparent Ki of 142 mM. Salicylic acid inhib- is known that PMNs release the potent chemokinetic and ited Isc with an apparent Ki of 646 mM. We determined chemoattractant, leukotriene B during an inflammatory re- whether ibuprofen would also inhibit the forskolin-stimu- sponse (1) resulting in the further migration of inflammatory lated Isc in primary cultures of mouse trachea epithelia cells. Cromwell et al. (2) have demonstrated the existence of (MTE) and human bronchial epithelia (HBE). Similar to the leukotrienes in the sputum of CF patients. In addition to our results in T84 cells, ibuprofen (500 mM) inhibited the the migrating granulocytes themselves potentially causing forskolin-induced Isc in MTEs and HBEs by 5964% (n 5 damage to the airway epithelium, Metchnikoff first hypothe- 11) and 3966% (n 5 8), respectively. Nystatin was em- sized in 1887 that the products released from the invading ployed to selectively permeabilize the basolateral or apical granulocytes might be capable of injuring the host tissue as membrane to determine the effect of ibuprofen on apical well (3). More recently, the oxidative metabolites of arachi- 2 1 Cl (ICl) and basolateral K (IK) currents after stimulation donic acid and the inflammatory cell-derived proteases have by forskolin. After forskolin stimulation, ibuprofen (500 been implicated in the destruction and shedding of the airway mM) reduced both the ICl and IK; reducing ICl and IK by 60 epithelia observed in CF (3–7). Based on these observations, it and 15%, respectively. To determine whether this inhibition has been proposed that anti-inflammatory drugs might be use- of ICl was due to the inhibition of CFTR, the effects of ibu- ful in CF therapy. The nonsteroidal anti-inflammatory drug profen and salicylic acid on CFTR Cl2 channels in excised, (NSAID) ibuprofen is known to inhibit 5-lipoxygenase and inside-out patches from L-cells were evaluated. Ibuprofen hence leukotriene formation (8) suggesting that ibuprofen (300 mM) reduced CFTR Cl2 current by 60616% and this may be useful in the treatment of CF. Ibuprofen was initially was explained by a short-lived block (z 1.2 ms) which shown to attenuate the inflammatory response to P. aerugi- causes an apparent reduction in single channel amplitude nosa challenge in both a mouse (9) and rat (10) model without from 1.0760.04 pA to 0.5960.04 pA (n 5 3). Similarly, sali- affecting the clearance or pulmonary burden of the pathogen. cylic acid (3 mM) reduced CFTR Cl2 current by 5068% These results led to a clinical trial in CF patients where it was with an apparent reduction in single channel amplitude shown that high-dose (50–100 mg/ml plasma) ibuprofen from 1.0860.03 pA to 0.4860.06 pA (n 5 4). Based on these slowed the annual rate of change in forced expiratory volume results, we conclude that the NSAIDs ibuprofen and sali- in one second (FEV1) in patients with mild lung disease while cylic acid inhibit cAMP-mediated Cl2 secretion in human having no apparent adverse effects (11). In a second clinical colonic and airway epithelia via a direct inhibition of CFTR trial to assess pharmacokinetics and cohort therapy experi- Cl2 channels as well as basolateral membrane K1 channels. ence, plasma ibuprofen concentrations as high as 150 mg/ml This may reduce their efficacy in conjunction with other were reported (12). therapeutic strategies designed to increase CFTR expres- While NSAIDs are widely used over-the-counter medica- sion and/or function in secretory epithelia. (J. Clin. Invest. tions, their use is known to result in intestinal inflammation 1998. 102:679–687.) Key words: CFTR • chloride secretion • and injury (13–15). This effect is believed to be caused by an intestine • airway • ibuprofen increased mucosal permeability (16). Paradoxically, it has been speculated that this is due to the inhibition of the cyclooxygen- ase-dependent oxidation of arachidonic acid resulting in the Address correspondence to Daniel C. Devor, Ph.D., Department of depletion of endogenous prostaglandins (13). In addition to Cell Biology and Physiology, S312 BST, 3500 Terrace Street, Univer- their effects on the cyclooxygenase- and lipoxygenase-depen- sity of Pittsburgh, Pittsburgh, PA 15261. Phone: 412-383-8755; FAX: dent oxidation of arachidonic acid, the NSAIDs are structur- 1 412-648-8330; E-mail: dd2 @pitt.edu B.D. Schultz’s current address 2 is Department of Anatomy and Physiology, Kansas State University, ally related to the known Cl channel blockers, diphenyl- 1600 Denison Avenue, VMS 228, Manhattan, KS 66506; E-mail: [email protected] 1. Abbreviations used in this paper: 293B, trans-6-cyano-4-(N-ethyl- Received for publication 22 December 1997 and accepted in re- sulphonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane; CF, cys- vised form 2 June 1998. tic fibrosis; CFTR, cystic fibrosis transmembrane conductance regula- tor; FEV1, forced expiratory volume in one second; HBE, human 2 J. Clin. Invest. bronchial epithelium; HPC, human placental collagen; ICl, Cl cur- 1 © The American Society for Clinical Investigation, Inc. rents; IK, K currents; Isc, short circuit current; MTE, murine tracheal 0021-9738/98/08/0679/09 $2.00 epithelium; NSAID, nonsteroidal anti-inflammatory drug; PDte, trans- Volume 102, Number 4, August 1998, 679–687 epithelial potential difference; PKA, protein kinase A; PMNs, poly- http://www.jci.org morphonuclear leukocytes. Ibuprofen Inhibits CFTR 679 amine-2-carboxylate and 5-nitro-2-(3-phenylpropylamino)- Sepra, Inc., Cedex, France) and an air interface at the apical mem- benzoate (17). Also, the NSAIDs, niflumic acid and flufenamic brane established. The media bathing the basolateral surface was acid are known inhibitors of the Ca21-dependent Cl2 channel changed every 48 h. Measurements of Isc were performed after z 10– in Xenopus oocytes (18). These results suggested that the 20 additional days in culture. structurally related NSAID ibuprofen may similarly affect ion Isc measurements. Costar transwell cell culture inserts were mounted in an Ussing chamber (Jim’s Instruments, Iowa City, IA) transport across epithelia. Thus, we determined the effect of 2 and the monolayers continuously short-circuited (University of Iowa, ibuprofen on Cl secretion in both human colonic and airway Department of Bioengineering, Iowa City, IA). Transepithelial resis- epithelia. We demonstrate that ibuprofen, at a pharmacologi- tance was measured by periodically applying a 5-mV pulse, and the 2 cally relevant concentration, inhibits cAMP-dependent Cl se- resistance calculated using Ohm’s law. The bath solution contained cretion across human colonic and airway epithelia and that this (in mM): 120 NaCl, 25 NaHCO3, 3.3 KH2PO4, 0.8 K2HPO4, 1.2 inhibition is due at least in part to the blocking of the cystic fi- MgCl2, 1.2 CaCl2, and 10 glucose. The pH of this solution was 7.4 2 brosis transmembrane conductance regulator (CFTR) Cl when gassed with a mixture of 95% O2–5% CO2 at 378C. The effects 2 channel. of forskolin, ibuprofen, and glibenclamide on apical membrane Cl currents (ICl) were assessed after permeabilization of the serosal membrane with nystatin (360 mg/ml), and the establishment of a mu- Methods cosa-to-serosa Cl2 concentration gradient. Serosal NaCl was replaced by equimolar Na-gluconate. Nystatin was added to the serosal mem- T84 cell culture. T84 cells were grown in DME and Ham’s F-12 (1:1) brane 15–30 min before the addition of drugs (20). Successful perme- supplemented with 15 mM Hepes, 14 mM NaHCO3, and 10% FBS.
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