Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa

Yael Pewzner-Jung, Shaghayegh Tavakoli Tabazavareh, Heike Grassmé, Katrin Anne Becker, Lukasz Japtok, Jörg Steinmann, Tammar Joseph, Stephan Lang, Burkhard Tuemmler, Edward H. Schuchman, Alex B. Lentsch, Burkhard Kleuser, Michael J. Edwards, Anthony H. Futerman, Erich Gulbins

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P. aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P. aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.

Original languageEnglish
Pages (from-to)1205-1214
Number of pages10
JournalEMBO Molecular Medicine
Volume6
Issue number9
DOIs
StatePublished - 2014

Keywords

  • Cystic fibrosis
  • Long chain base
  • Lung infection
  • Pseudomonas aeruginosa
  • Sphingosine

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