title: New use for an old drug: COX-independent anti-inflammatory effects of sulindac in models of cystic fibrosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Overall, sulindac decrease lung inflammation by a mechanism independent of cycolooxygenase. This drug could be beneficially employed in CF.
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Rocca
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Manin
authors.affiliation: DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Hulin
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.|AP-HP, Hôpital H. Mondor-A. Chenevier, Pôle de Biologie, Créteil, France.
authors.forename: Abdel
authors.initials: A
authors.lastname: Aissat
authors.affiliation: Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Verbecq-Morlot
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.|CHIC, service d'ORL, Créteil, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Prulière-Escabasse
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|McGill University, Montréal, Canada.
authors.forename: Adeline
authors.initials: A
authors.lastname: Wohlhuter-Haddad
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Ralph
authors.initials: R
authors.lastname: Epaud
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.|AP-HP, Hôpital H. Mondor-A. Chenevier, Pôle de Biologie, Créteil, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Fanen
authors.affiliation: Inserm, U955, Equipe 5, Créteil, France.|Université Paris Est, UPEC, Créteil, France.|DHU Ageing-Thorax-Vessel-Blood, Créteil, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Tarze
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013467:Sulindac / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D013467:Sulindac; D011451:Prostaglandin-Endoperoxide Synthases