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Am J Physiol Lung Cell Mol Physiol (August 18, 2006). doi:10.1152/ajplung.00403.2005
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Submitted on September 19, 2005
Accepted on August 11, 2006

CFTR inhibition mimics the cystic fibrosis inflammatory profile

Aura Perez1*, Amanda C Issler1, Calvin U Cotton1, Thomas J Kelley1, Alan S. Verkman1, and Pamela B Davis1

1 Pediatrics, Case Western Reserve University, Cleveland, Ohio, United States; Physiology & Biophysics, Case Western Reserve University, Cleveland, Ohio, United States; Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States; Molecular Biology & Microbiology, Case Western Reserve University, Cleveland, Ohio, United States; Medicine and Physiology, University of California, San Francisco, California, United States

* To whom correspondence should be addressed. E-mail: aura.perez{at}case.edu.

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 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 four-fold decrease in Smad3 expression (p = 0.02), a 3-fold increase in RhoA expression, and increased NF-{kappa}B nuclear translocation upon TNF{alpha}/IL-1{beta} stimulation (p < 0.000001). CFTR inhibition by CFTRinh-172 over this period does not increase ENaC activity, so lack of Cl- conductance alone can mimic the inflammatory CF phenotype. CFTRinh-172 does not affect IL-8, IL-6 or GM-CSF 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 LDH, trypan blue, ciliary activity, EM 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.




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