Published ahead of print on July 26, 2007, doi:10.1165/rcmb.2007-0036OC
Am. J. Respir. Cell Mol. Biol., Volume 38, Number 1, January 2008, 47-56
A more recent version of this article appeared on January 1, 2008
Submitted on February 8, 2007
Revised on July 25, 2007
Fenretinide Corrects Newly Found Ceramide Deficiency in Cystic Fibrosis
Claudine Guilbault1, Juan B De Sanctis2, Gabriella Wojewodka3, Zienab Saeed3, Claude Lachance1, Thomas A Skinner1, Regina M Vilela4, Stan Kubow4, Larry C Lands5, Marian Hajduch6, Elias Matouk7, and Danuta Radzioch8*
1 Department of Experimental Medicine, McGill University Health Center, Montreal General Hospital Research Institute, Montreal, Canada,
2 Institute of Immunology, Central University of Venezuela, Caracas, Venezuela,
3 Department of Human Genetics, McGill University Health Center, Montreal, Canada,
4 McGill University, School of Dietetics and Human Nutrition, Montreal, Canada,
5 Department of Pediatrics, McGill University Health Center, Montreal, Canada,
6 Department of Pediatrics, Laboratory of Experimental Medicine, Palacky University in Olomouc, Olomouc, Czech Republic,
7 Adult Cystic Fibrosis Clinic, McGill University Health Center, Montreal, Canada,
8 Department of Experimental Medicine, McGill University Health Center, Montreal General Hospital Research Institute, Montreal, Canada; Department of Human Genetics, McGill University Health Center, Montreal, Canada
* To whom correspondence should be addressed. E-mail: danuta.radzioch{at}muhc.mcgill.ca.
Chronic and persistent lung infections cause the majority of morbidity and mortality in cystic fibrosis patients. Galactosyl ceramide has been previously shown to be involved in Pseudomonas internalization. Therefore, we assessed ceramide levels in the plasma of CF patients and compared them to healthy volunteers using HPLC followed by Mass Spectrometry. Our results demonstrate that CF patients display significantly lower levels of several ceramide sphingolipid species, specifically C14:0, C20:1, C22:0, C22:1, 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 to 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 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 CF patients but also demonstrate a pharmacological mean to correct this defect in Cftr-knockout mice. Our data provides a strong rationale for clinical intervention that may benefit cystic fibrosis patients suffering from CF lung disease.
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Copyright © 2007 American Thoracic Society.
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