help button home button
AJRCMB
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS

Published ahead of print on July 26, 2007, doi:10.1165/rcmb.2007-0036OC
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
2007-0036OCv1
38/1/47    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guilbault, C.
Right arrow Articles by Radzioch, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guilbault, C.
Right arrow Articles by Radzioch, D.
American Journal of Respiratory Cell and Molecular Biology. Vol. 38, pp. 47-56, 2008
© 2008 American Thoracic Society
DOI: 10.1165/rcmb.2007-0036OC

Fenretinide Corrects Newly Found Ceramide Deficiency in Cystic Fibrosis

Claudine Guilbault1,*, Juan B. De Sanctis2,*, Gabriella Wojewodka3, Zienab Saeed3, Claude Lachance1, Thomas A. A. Skinner1, Regina M. Vilela4, Stan Kubow4, Larry C. Lands5, Marian Hajduch6, Elias Matouk7 and Danuta Radzioch1,3

1 Department of Experimental Medicine, 3 Department of Human Genetics, 5 Department of Pediatrics, and 7 Adult Cystic Fibrosis Clinic, McGill University Health Center, Montreal General Hospital Research Institute, Montreal, Quebec, Canada; 2 Central University of Venezuela, Institute of Immunology, Caracas, Venezuela; 4 School of Dietetics and Human Nutrition, McGill University, Montreal, Quebec, Canada; 6 Palacky University in Olomouc, Department of Pediatrics, Laboratory of Experimental Medicine, Olomouc, Czech Republic

Correspondence and requests for reprints should be addressed to Danuta Radzioch, Ph.D., McGill University Health Center, Montreal General Hospital Research Institute, 1650 Cedar Avenue, Room L11-218, Montreal, PQ, H3G 1A4 Canada. E-mail: danuta.radzioch{at}muhc.mcgill.ca

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.

Key Words: Cftr-KO mice • cystic fibrosis • ceramide • Pseudomonas aeruginosa • fenretinide


CLINICAL RELEVANCE

We report a novel deficiency in ceramide in patients with cystic fibrosis (CF). Fenretinide can correct this defect in Cftr-knockout mice, improving their ability to control Pseudomonas aeruginosa lung infection. This provides a strong rationale for clinical intervention that may benefit patients with CF.

 






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Crit. Care Med.
Copyright © 2008 American Thoracic Society.