Article abstract
Nature Medicine 14, 382 - 391 (2008)
Published online: 30 March 2008 | doi:10.1038/nm1748
Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis
Volker Teichgräber1,11, Martina Ulrich2,11, Nicole Endlich3, Joachim Riethmüller4, Barbara Wilker1, Cheyla Conceição De Oliveira–Munding2, Anna M van Heeckeren5, Mark L Barr6, Gabriele von Kürthy7, Kurt W Schmid8, Michael Weller7, Burkhard Tümmler9, Florian Lang10, Heike Grassme1, Gerd Döring2,11 & Erich Gulbins1,11
Abstract
Microbial lung infections are the major cause of morbidity and mortality in the hereditary metabolic disorder cystic fibrosis, yet the molecular mechanisms leading from the mutation of cystic fibrosis transmembrane conductance regulator (CFTR) to lung infection are still unclear. Here, we show that ceramide age-dependently accumulates in the respiratory tract of uninfected Cftr-deficient mice owing to an alkalinization of intracellular vesicles in Cftr-deficient cells. This change in pH results in an imbalance between acid sphingomyelinase (Asm) cleavage of sphingomyelin to ceramide and acid ceramidase consumption of ceramide, resulting in the higher levels of ceramide. The accumulation of ceramide causes Cftr-deficient mice to suffer from constitutive age-dependent pulmonary inflammation, death of respiratory epithelial cells, deposits of DNA in bronchi and high susceptibility to severe Pseudomonas aeruginosa infections. Partial genetic deficiency of Asm in Cftr-/-Smpd1+/- mice or pharmacological treatment of Cftr-deficient mice with the Asm blocker amitriptyline normalizes pulmonary ceramide and prevents all pathological findings, including susceptibility to infection. These data suggest inhibition of Asm as a new treatment strategy for cystic fibrosis.
- Department of Molecular Biology, Hufelandstrasse 55, University of Duisburg-Essen, 45122 Essen, Germany.
- Institute of Medical Microbiology and Hygiene, Wilhelmstrasse 31, 72074 Tübingen, Germany.
- Department of Anatomy, Friedrich-Loeffler-Strasse 23c, University of Greifswald, 17487 Greifswald, Germany.
- Children`s Clinic, Auf dem Schnarrenberg, University of Tübingen, 72076 Tübingen, Germany.
- Case Western Reserve University, Biomedical Research Building 827, 10900 Euclid Avenue, Cleveland, Ohio 44106–4948, USA.
- Department of Cardiothoracic Surgery, University of Southern California, 1520 San Pablo Street, Suite 4300, Los Angeles, California 90033, USA.
- Department of Neurology, Auf dem Schnarrenberg, University of Tübingen, 72076 Tübingen, Germany.
- Department of Pathology and Neuropathology, Hufelandstrasse 55, University of Duisburg-Essen, 45122 Essen, Germany.
- Medical University School, Carl-Neuberg-Strasse, 30625 Hannover, Germany.
- Department of Physiology, Gmelinstrasse 5, University of Tübingen, 72076 Tübingen, Germany.
- These authors contributed equally to this work.
Correspondence to: Erich Gulbins1,11 e-mail: erich.gulbins@uni-due.de