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New use for an old drug: COX‐independent anti‐inflammatory effects of sulindac in models of cystic fibrosis
Author(s) -
Rocca Jérémy,
Manin Sylvie,
Hulin Anne,
Aissat Abdel,
VerbecqMorlot Wilfried,
PrulièreEscabasse Virginie,
WohlhuterHaddad Adeline,
Epaud Ralph,
Fanen Pascale,
Tarze Agathe
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13464
Subject(s) - sulindac , cystic fibrosis , in vivo , cyclooxygenase , inflammation , ibuprofen , pharmacology , medicine , secretion , interleukin 8 , interleukin 6 , lung , immunology , biology , enzyme , biochemistry , microbiology and biotechnology , nonsteroidal
Background and Purpose Pulmonary disease is the main cause of morbidity and mortality in cystic fibrosis (CF) patients due to exacerbated inflammation. To date, the only anti‐inflammatory drug available to CF patients is high‐dose ibuprofen, which can slow pulmonary disease progression, but whose cyclooxygenase‐dependent digestive adverse effects limit its clinical use. Here we have tested sulindac, another non‐steroidal anti‐inflammatory drug with an undefined anti‐inflammatory effect in CF airway epithelial cells. Experimental Approach Using in vitro and in vivo models, we NF‐κB activity and IL‐8 secretion. In HeLa‐F508del cells, we performed luciferase reporter gene assays in order to measure i) IL‐8 promoter activity, and ii) the activity of synthetic promoter containing NF‐κB responsive elements. We quantified IL‐8 secretion in airway epithelial CFBE cells cultured at an air‐liquid interface and in a mouse model of CF. Key Results Sulindac inhibited the transcriptional activity of NF‐κB and decreased IL‐8 transcription and secretion in TNF‐α stimulated CF cells via a cyclooxygenase‐independent mechanism. This effect was confirmed in vivo in a mouse model of CF induced by intra‐tracheal instillation of LPS, with a significant decrease of the induction of mRNA for MIP‐2, following treatment with sulindac. Conclusion and Implications Overall, sulindac decrease lung inflammation by a mechanism independent of cycolooxygenase. This drug could be beneficially employed in CF.