AJP - Lung Add DOIs to your references at manuscript stage!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol 292: L383-L395, 2007. First published August 18, 2006; doi:10.1152/ajplung.00403.2005
1040-0605/07 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
292/2/L383    most recent
00403.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (34)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Perez, A.
Right arrow Articles by Davis, P. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Perez, A.
Right arrow Articles by Davis, P. B.

EDITORIAL FOCUS

CFTR inhibition mimics the cystic fibrosis inflammatory profile

Aura Perez,1 Amanda C. Issler,1 Calvin U. Cotton,1,2 Thomas J. Kelley,1,3 Alan S. Verkman,5 and Pamela B. Davis1,2,4

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, CFTRinh-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-{kappa}B nuclear translocation upon TNF-{alpha}/IL-1beta stimulation (P < 0.000001). CFTR inhibition by CFTRinh-172 over this period does not increase epithelial sodium channel activity, so lack of Cl– conductance alone can mimic the inflammatory CF phenotype. CFTRinh-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 CFTRinh-172 effects on cytokines are not direct. Five-day treatment with CFTRinh-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


Address for reprint requests and other correspondence: A. Perez, Dept. of Pediatrics, School of Medicine, Case Western Reserve Univ., BRB Bldg. R829, 10900 Euclid Ave., Cleveland, OH 44106-4948 (e-mail: aura.perez{at}case.edu)




This article has been cited by other articles:


Home page
 Eur Respir JHome page
P. Henno, C. Maurey, C. Danel, P. Bonnette, R. Souilamas, M. Stern, C. Delclaux, M. Levy, and D. Israel-Biet
Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-{kappa}B and endothelin-1
Eur. Respir. J., December 1, 2009; 34(6): 1329 - 1337.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
D. P. Nichols, A. G. Ziady, S. L. Shank, J. F. Eastman, and P. B. Davis
The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease
Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L828 - L836.
[Abstract] [Full Text] [PDF]

Home page
 MicrobiologyHome page
K. E. Keith, D. W. Hynes, J. E. Sholdice, and M. A. Valvano
Delayed association of the NADPH oxidase complex with macrophage vacuoles containing the opportunistic pathogen Burkholderia cenocepacia
Microbiology, April 1, 2009; 155(4): 1004 - 1015.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
E. M. Bruscia, P.-X. Zhang, E. Ferreira, C. Caputo, J. W. Emerson, D. Tuck, D. S. Krause, and M. E. Egan
Macrophages Directly Contribute to the Exaggerated Inflammatory Response in Cystic Fibrosis Transmembrane Conductance Regulator-/- Mice
Am. J. Respir. Cell Mol. Biol., March 1, 2009; 40(3): 295 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
T. R. Bartling and M. L. Drumm
Oxidative Stress Causes IL8 Promoter Hyperacetylation in Cystic Fibrosis Airway Cell Models
Am. J. Respir. Cell Mol. Biol., January 1, 2009; 40(1): 58 - 65.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 FASEB J.Home page
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]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 J. Pharmacol. Exp. Ther.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 Proc Am Thorac SocHome page
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]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
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]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2007 by the American Physiological Society.