title: Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis.
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.
authors: Department of Molecular Biology, Hufelandstrasse 55, University of Duisburg-Essen, 45122 Essen, Germany.
authors: Volker
authors: V
authors: Teichgräber
authors: Martina
authors: M
authors: Ulrich
authors: Nicole
authors: N
authors: Endlich
authors: Joachim
authors: J
authors: Riethmüller
authors: Barbara
authors: B
authors: Wilker
authors: Cheyla Conceição
authors: CC
authors: De Oliveira-Munding
authors: Anna M
authors: AM
authors: van Heeckeren
authors: Mark L
authors: ML
authors: Barr
authors: Gabriele
authors: G
authors: von Kürthy
authors: Kurt W
authors: KW
authors: Schmid
authors: Michael
authors: M
authors: Weller
authors: Burkhard
authors: B
authors: Tümmler
authors: Florian
authors: F
authors: Lang
authors: Heike
authors: H
authors: Grassme
authors: Gerd
authors: G
authors: Döring
authors: Erich
authors: E
authors: Gulbins
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D016923:Cell Death; D002518:Ceramides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics; D004247:DNA / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018181:Mice, Inbred CFTR; D018410:Pneumonia, Bacterial / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011552:Pseudomonas Infections / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics
chemical_list: D002518:Ceramides; D018836:Inflammation Mediators; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004247:DNA; D013108:Sphingomyelin Phosphodiesterase