Ibuprofen rescues mutant cystic fibrosis transmembrane conductance regulator trafficking

Graeme W. Carlile*, Renaud Robert, Julie Goepp, Elizabeth Matthes, Jie Liao, Bart Kus, Sean D. Macknight, Daniela Rotin, John W. Hanrahan, David Y. Thomas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Background: Small molecules as shown by VX809 can rescue the mislocalization of F508del-CFTR. The aim of this study was to identify correctors with a clinical history and their targets of action. Methods: CFTR correctors were screened using two F508del-CFTR expressing cell based HTS assays. Electrophysiological studies using CFBE41o- and HBE cells and in-vivo mouse assays confirmed CFTR rescue. The target of action was attained using pharmacological inhibitors and siRNA to specific genes. Results: Ibuprofen was identified as a CFTR corrector. Ibuprofen treatment of polarized CFBE41o- monolayers increased the short-circuit current (Isc) response to stimulation. In vivo CF mice treatment with ibuprofen restored the CFTR trafficking. SiRNA knock down of cyclooxygenase expression caused partial F508del-CFTR correction. Conclusion: These studies show that ibuprofen is a CFTR corrector and that it causes correction by COX-1 inhibition. Hence ibuprofen may be suitable to be part of a future CF combination therapy.

Original languageEnglish (US)
Pages (from-to)16-25
Number of pages10
JournalJournal of Cystic Fibrosis
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Cystic fibrosis
  • NSAID
  • Protein folding
  • Protein trafficking

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

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