Quick Search:

uzh logo
Browse by:

The deadline for the annual report 2015 is January 31st, 2016

Zurich Open Repository and Archive

Maintenance: Tuesday, 16.2.2015, 06:00-08:00

Maintenance work on various system components of ZORA. During this time there will be a brief unavailability for about 1 hour. Please be patient.

Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-4016

Teichgräber, V; Ulrich, M; Endlich, N; Riethmüller, J; Wilker, B; De Oliveira-Munding, C C; van Heeckeren, A M; Barr, M L; von Kürthy, G; Schmid, K W; Weller, M; Tümmler, B; Lang, F; Grassme, H; Döring, G; Gulbins, E (2008). Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nature Medicine, 14(4):382-391.

Accepted Version
View at publisher
Accepted Version


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.


227 citations in Web of Science®
243 citations in Scopus®
Google Scholar™



87 downloads since deposited on 14 Nov 2008
17 downloads since 12 months

Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Date:April 2008
Deposited On:14 Nov 2008 12:47
Last Modified:27 Nov 2013 21:39
Publisher:Nature Publishing Group
Publisher DOI:10.1038/nm1748
PubMed ID:18376404

Users (please log in): suggest update or correction for this item

Repository Staff Only: item control page