title: Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa.
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.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel erich.gulbins@uni-due.de yael.pewzner-jung@weizmann.ac.il.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Shaghayegh
authors.initials: S
authors.lastname: Tavakoli Tabazavareh
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Grassmé
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Katrin Anne
authors.initials: KA
authors.lastname: Becker
authors.affiliation: Department of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Japtok
authors.affiliation: Department of Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinmann
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tammar
authors.initials: T
authors.lastname: Joseph
authors.affiliation: Department of Otorhinolaryngology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Lang
authors.affiliation: Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tuemmler
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
authors.affiliation: Department of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
authors.affiliation: Department of Surgery, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany Department of Surgery, University of Cincinnati, Cincinnati, OH, USA erich.gulbins@uni-due.de yael.pewzner-jung@weizmann.ac.il.
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D055573:Acid Ceramidase / Q000008:administration & dosage / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D002518:Ceramides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism; D004198:Disease Susceptibility; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D011552:Pseudomonas Infections / Q000150:complications / Q000276:immunology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa; D012141:Respiratory Tract Infections / Q000150:complications / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014132:Trachea / Q000378:metabolism
chemical_list: D002518:Ceramides; D011409:Propylene Glycols; D055573:Acid Ceramidase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Pseudomonas aeruginosa; cystic fibrosis; long chain base; lung infection; sphingosine
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