Fenretinide Corrects Newly Found Ceramide Deficiency in Cystic Fibrosis
| Autor: | Thomas A. A. Skinner, Danuta Radzioch, Claudine Guilbault, Zienab Saeed, Stan Kubow, Juan B. De Sanctis, Elias Matouk, Gabriella Wojewodka, Marian Hajduch, Larry C. Lands, Regina Maria Vilela, Claude Lachance |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Adult
Male Pulmonary and Respiratory Medicine medicine.medical_specialty Ceramide Cystic Fibrosis Fenretinide Clinical Biochemistry Cystic Fibrosis Transmembrane Conductance Regulator Ileum Biology Ceramides Cystic fibrosis Mass Spectrometry Mice chemistry.chemical_compound In vivo Cell Line Tumor Internal medicine medicine Animals Anticarcinogenic Agents Humans Mice Inbred CFTR Pseudomonas Infections Molecular Biology Chromatography High Pressure Liquid Mice Knockout Sphingolipids Lung Cell Biology Middle Aged medicine.disease Sphingolipid In vitro medicine.anatomical_structure Endocrinology chemistry Organ Specificity Pseudomonas aeruginosa Immunology Female lipids (amino acids peptides and proteins) |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 38:47-56 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2007-0036oc |
| Popis: | Chronic and persistent lung infections cause the majority of morbidity and mortality in patients with cystic fibrosis (CF). Galactosyl ceramide has been previously shown to be involved in Pseudomonas internalization. Therefore, we assessed ceramide levels in the plasma of patients with CF and compared them to healthy volunteers using high-performance liquid chromatography followed by mass spectrometry. Our results demonstrate that patients with CF display significantly lower levels of several ceramide sphingolipid species, specifically C14:0, C20:1, C22:0, C22:1, and C24:0 ceramides, and dihydroxy ceramide (DHC16:0). We report that Cftr-knockout mice display diminished ceramide levels in CF-related organs (lung, pancreas, ileum, and plasma) compared with their littermate controls. Since it has been previously reported that in vitro treatment with fenretinide induced ceramide in neuroblastoma cell lines, we decided to test this drug in vivo using our Cftr-knockout mice in an attempt to correct this newly identified defect in ceramide levels. We demonstrate that treatment with fenretinide is able to increase ceramide concentrations in CF-related organs. We further assessed the biological effect of fenretinide on the ability of Cftr-knockout mice to combat lung infection with P. aeruginosa. Our data show dramatic improvement in the ability of Cftr-knockout mice to control P. aeruginosa infection. Overall, these findings not only document a novel deficiency in several ceramide species in patients with CF, but also demonstrate a pharmacologic means to correct this defect in Cftr-knockout mice. Our data provide a strong rationale for clinical intervention that may benefit patients with CF suffering from CF lung disease. |
| Databáze: | OpenAIRE |
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