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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.

New use for an old drug: COX‐independent anti‐inflammatory effects of sulindac in models of cystic fibrosis