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Fenretinide Corrects Newly Found Ceramide Deficiency in Cystic Fibrosis

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.