Details

Autor(en) / Beteiligte

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

Titel

Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa

Ist Teil von

• EMBO molecular medicine, 2014-09, Vol.6 (9), p.1205-1214

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2014

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• 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. Synopsis Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase. Sphingosine is present on the luminal side of trachea and bronchi epithelia in healthy individuals. Sphingosine level is reduced on trachea and bronchi epithelia in diseases such as cystic fibrosis or in mice lacking ceramide synthase 2. Acid ceramidase or sphingosine inhalation corrects sphingosine levels in cystic fibrosis and ceramide synthase 2‐deficient mice, prevents their infection with Pseudomonas aeruginosa and cures an existing Pseudomonas aeruginosa infection. Sphingosine kills a broad spectrum of pathogens at nanomolar to low micromolar concentrations including Pseudomomas aeruginosa, Acinetobacter baumannii, Haemophilus influenzae, Moraxella catarrhalis and Burkholderia cepacia. Sphingosine functions as an important anti‐bacterial agent in healthy airways but this defence mechanism is lost in cystic fibrosis. The sensitivity of cystic fibrosis mice to infection can be corrected by inhalation of sphingosine or acid ceramidase.