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We previously showed that alveolar macrophages (AM) from children with PBB or BE have a similar significant defect in phagocytic capacity, with proinflammatory associations. We hypothesized that the mechanisms responsible for this defect involve dysregulation of the sphingosine\u20101\u2010phosphate (S1P) signaling pathway, as we have found in adult inflammatory lung diseases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We employed a Custom TaqMan OpenArray to investigate gene expression of S1P\u2010generating enzymes: sphingosine kinases (SPHK) 1\/2, S1P phosphatase 2 (<jats:italic>SGPP2)<\/jats:italic>, S1P lyase 1 (<jats:italic>SGPL1<\/jats:italic>), S1P receptors (<jats:italic>S1PR<\/jats:italic>) 1\/2\/4\/5; proinflammatory cytokines TNF\u2010\u03b1 (<jats:italic>TNF<\/jats:italic>) and IFN\u03b3 (<jats:italic>IFNG<\/jats:italic>), the cytotoxic mediator granzyme B (<jats:italic>GZMB<\/jats:italic>), and inflammasomes <jats:italic>AIM2<\/jats:italic> and <jats:italic>NLRP3<\/jats:italic>, in bronchoalveolar lavage from 15 children with BE, 15 with PBB and 17 age\u2010matched controls, and determined association with clinical\/demographic variables and airway inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>Significantly increased expression of <jats:italic>S1PR1<\/jats:italic>, <jats:italic>S1PR2<\/jats:italic>, and <jats:italic>SPHK1<\/jats:italic> was noted in PBB and BE AM vs controls with increased <jats:italic>SGPP2<\/jats:italic> only in PBB. <jats:italic>TNF<\/jats:italic>, <jats:italic>IFNG<\/jats:italic>, <jats:italic>AIM2<\/jats:italic>, and <jats:italic>NLRP3<\/jats:italic> were significantly increased in both disease groups with increased <jats:italic>GZMB<\/jats:italic> only in PBB. There were no significant differences in the expression of any other S1P\u2010related mediator between groups. There were significant positive associations between <jats:italic>Haemophilus influenzae<\/jats:italic> growth and expression of <jats:italic>S1PR1<\/jats:italic> and <jats:italic>NLRP3<\/jats:italic>; between <jats:italic>S1PR1<\/jats:italic> and <jats:italic>S1PR2<\/jats:italic>, <jats:italic>NLRP3<\/jats:italic> and <jats:italic>IFNG<\/jats:italic>; between <jats:italic>S1PR2<\/jats:italic> and <jats:italic>AIM2<\/jats:italic>, <jats:italic>SPHK1<\/jats:italic>, and <jats:italic>SPHK2<\/jats:italic>; and between <jats:italic>SPHK1<\/jats:italic> and <jats:italic>GZMB<\/jats:italic>, <jats:italic>IFNG<\/jats:italic>, <jats:italic>AIM2<\/jats:italic>, and <jats:italic>NLRP3<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Children with PBB and BE share similar S1P\u2010associated gene expression profiles. AM phagocytic dysfunction and inflammation in these children may occur due to dysregulated S1P signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ppul.24728","type":"journal-article","created":{"date-parts":[[2020,3,16]],"date-time":"2020-03-16T17:40:24Z","timestamp":1584380424000},"page":"1414-1423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sphingosine signaling dysfunction in airway cells as a potential contributor to progression from protracted bacterial bronchitis to bronchiectasis in children"],"prefix":"10.1002","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9401-298X","authenticated-orcid":false,"given":"Sandra","family":"Hodge","sequence":"first","affiliation":[{"name":"Lung Research Unit, Department of Thoracic Medicine Royal Adelaide Hospital Adelaide South Australia Australia"},{"name":"Faculty\u00a0of Medicine The University of Adelaide Adelaide South Australia 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