Fenretinide corrects newly found ceramide deficiency in cystic fibrosis.
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.
McGill University Health Center, Montreal General Hospital Research Institute, 1650 Cedar Avenue, Room L11-218, Montreal, PQ, H3G 1A4 Canada.
Claudine
C
Guilbault
Juan B
JB
De Sanctis
Gabriella
G
Wojewodka
Zienab
Z
Saeed
Claude
C
Lachance
Thomas A A
TA
Skinner
Regina M
RM
Vilela
Stan
S
Kubow
Larry C
LC
Lands
Marian
M
Hajduch
Elias
E
Matouk
Danuta
D
Radzioch
D000328:Adult; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002518:Ceramides / Q000097:blood / Q000172:deficiency*; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D017313:Fenretinide / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D011552:Pseudomonas Infections / Q000097:blood* / Q000235:genetics; D011550:Pseudomonas aeruginosa; D013107:Sphingolipids / Q000097:blood / Q000172:deficiency*
D016588:Anticarcinogenic Agents; D002518:Ceramides; D013107:Sphingolipids; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017313:Fenretinide