HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/2/L383    most recent 00403.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Perez, A. Articles by Davis, P. B. Search for Related Content PubMed PubMed Citation Articles by Perez, A. Articles by Davis, P. B.

EDITORIAL FOCUS

CFTR inhibition mimics the cystic fibrosis inflammatory profile

Departments of ¹Pediatrics, ²Physiology & Biophysics, ³Pharmacology, and ⁴Molecular Biology & Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and ⁵Departments of Medicine and Physiology, University of California, San Francisco, California

Submitted 19 September 2005 ; accepted in final form 11 August 2006

Primary airway epithelial cells grown in air-liquid interface differentiate into cultures that resemble native epithelium morphologically, express ion transport similar to those in vivo, and secrete cytokines in response to stimuli. Comparisons of cultures derived from normal and cystic fibrosis (CF) individuals are difficult to interpret due to genetic differences besides CFTR. The recently discovered CFTR inhibitor, CFTR_inh-172, was used to create a CF model with its own control to test if loss of CFTR-Cl^– conductance alone was sufficient to initiate the CF inflammatory response. Continuous inhibition of CFTR-Cl^– conductance for 3–5 days resulted in significant increase in IL-8 secretion at basal (P = 0.006) and in response to 10⁹ Pseudomonas (P = 0.0001), a fourfold decrease in Smad3 expression (P = 0.02), a threefold increase in RhoA expression, and increased NF-B nuclear translocation upon TNF-/IL-1 stimulation (P < 0.000001). CFTR inhibition by CFTR_inh-172 over this period does not increase epithelial sodium channel activity, so lack of Cl^– conductance alone can mimic the inflammatory CF phenotype. CFTR_inh-172 does not affect IL-8, IL-6, or granulocyte/macrophage colony-stimulating factor secretion in two CF phenotype immortalized cell lines: 9/HTEo^– pCEP-R and 16HBE14o^– AS, or IL-8 secretion in primary CF cells, and inhibitor withdrawal abolishes the increased response, so CFTR_inh-172 effects on cytokines are not direct. Five-day treatment with CFTR_inh-172 does not affect cells deleteriously as evidenced by lactate dehydrogenase, trypan blue, ciliary activity, electron micrograph histology, and inhibition reversibility. Our results support the hypothesis that lack of CFTR activity is responsible for the onset of the inflammatory cascade in the CF lung.

inflammation; Pseudomonas; cytokines; cystic fibrosis transmembrane conductance regulator; epithelial sodium channel

This article has been cited by other articles:

				N. T. N. Trinh, A. Prive, E. Maille, J. Noel, and E. Brochiero EGF and K+ channel activity control normal and cystic fibrosis bronchial epithelia repair Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L866 - L880. [Abstract] [Full Text] [PDF]

				M. E. Manson, D. A. Corey, N. M. White, and T. J. Kelley cAMP-mediated regulation of cholesterol accumulation in cystic fibrosis and Niemann-Pick type C cells Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L809 - L819. [Abstract] [Full Text] [PDF]

				A. Perez, A. M. van Heeckeren, D. Nichols, S. Gupta, J. F. Eastman, and P. B. Davis Peroxisome proliferator-activated receptor-{gamma} in cystic fibrosis lung epithelium Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L303 - L313. [Abstract] [Full Text] [PDF]

				A. E. Chappell, M. Bunz, E. Smoll, H. Dong, C. Lytle, K. E. Barrett, and D. F. McCole Hydrogen peroxide inhibits Ca2+-dependent chloride secretion across colonic epithelial cells via distinct kinase signaling pathways and ion transport proteins FASEB J, June 1, 2008; 22(6): 2023 - 2036. [Abstract] [Full Text] [PDF]

				M. Mizumori, Y. Choi, P. H. Guth, E. Engel, J. D. Kaunitz, and Y. Akiba CFTR inhibition augments NHE3 activity during luminal high CO2 exposure in rat duodenal mucosa Am J Physiol Gastrointest Liver Physiol, June 1, 2008; 294(6): G1318 - G1327. [Abstract] [Full Text] [PDF]

				T. J. Miller and P. B. Davis FXYD5 modulates Na+ absorption and is increased in cystic fibrosis airway epithelia Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L654 - L664. [Abstract] [Full Text] [PDF]

				V. J. Broughton-Head, J. Shur, M. P. Carroll, J. R. Smith, and J. K. Shute Unfractionated heparin reduces the elasticity of sputum from patients with cystic fibrosis Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1240 - L1249. [Abstract] [Full Text] [PDF]

				K. Hybiske, Z. Fu, C. Schwarzer, J. Tseng, J. Do, N. Huang, and T. E. Machen Effects of cystic fibrosis transmembrane conductance regulator and {Delta}F508CFTR on inflammatory response, ER stress, and Ca2+ of airway epithelia Am J Physiol Lung Cell Mol Physiol, November 1, 2007; 293(5): L1250 - L1260. [Abstract] [Full Text] [PDF]

				C. Routaboul, C. Norez, P. Melin, M.-C. Molina, B. Boucherle, F. Bossard, S. Noel, R. Robert, C. Gauthier, F. Becq, et al. Discovery of {alpha}-Aminoazaheterocycle-Methylglyoxal Adducts as a New Class of High-Affinity Inhibitors of Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channels J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1023 - 1035. [Abstract] [Full Text] [PDF]

				S. Chatterjee, S. Baeter, and J. Bhattacharya Endothelial and epithelial signaling in the lung Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L517 - L519. [Abstract] [Full Text] [PDF]

				S. D. Sagel, J. F. Chmiel, and M. W. Konstan Sputum Biomarkers of Inflammation in Cystic Fibrosis Lung Disease Proceedings of the ATS, August 1, 2007; 4(4): 406 - 417. [Abstract] [Full Text] [PDF]

				M. C. Dechecchi, E. Nicolis, V. Bezzerri, A. Vella, M. Colombatti, B. M. Assael, Y. Mettey, M. Borgatti, I. Mancini, R. Gambari, et al. MPB-07 Reduces the Inflammatory Response to Pseudomonas aeruginosa in Cystic Fibrosis Bronchial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 615 - 624. [Abstract] [Full Text] [PDF]

				B. K. Rubin CFTR is a modulator of airway inflammation Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L381 - L382. [Full Text] [PDF]