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Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction
D. Garić, JB. De Sanctis, DC. Dumut, J. Shah, MJ. Peña, M. Youssef, BJ. Petrof, F. Kopriva, JW. Hanrahan, M. Hajduch, D. Radzioch,
Jazyk angličtina Země Nizozemsko
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
POP90155
CIHR - Canada
NV16-32302A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Odkazy
PubMed
31678518
DOI
10.1016/j.bbalip.2019.158538
Knihovny.cz E-zdroje
- MeSH
- aplikace orální MeSH
- buněčné linie MeSH
- cystická fibróza komplikace genetika patologie MeSH
- fenretinid aplikace a dávkování MeSH
- fosfolipidy metabolismus MeSH
- hlen metabolismus MeSH
- krysa rodu rattus MeSH
- kyselina arachidonová metabolismus MeSH
- kyseliny dokosahexaenové metabolismus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- mucin 5AC metabolismus MeSH
- mucin 5B metabolismus MeSH
- myši inbrední CFTR MeSH
- myši MeSH
- plíce účinky léků metabolismus patologie MeSH
- pneumonie mikrobiologie patologie prevence a kontrola MeSH
- pseudomonádové infekce mikrobiologie patologie prevence a kontrola MeSH
- Pseudomonas aeruginosa patogenita MeSH
- respirační sliznice cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cystic fibrosis (CF) is the most common genetic disease in Caucasians. CF is manifested by abnormal accumulation of mucus in the lungs, which serves as fertile ground for the growth of microorganisms leading to recurrent infections and ultimately, lung failure. Mucus in CF patients consists of DNA from dead neutrophils as well as mucins produced by goblet cells. MUC5AC mucin leads to pathological plugging of the airways whereas MUC5B has a protective role against bacterial infection. Therefore, decreasing the level of MUC5AC while maintaining MUC5B intact would in principle be a desirable mucoregulatory treatment outcome. Fenretinide prevented the lipopolysaccharide-induced increase of MUC5AC gene expression, without affecting the level of MUC5B, in a lung goblet cell line. Additionally, fenretinide treatment reversed the pro-inflammatory imbalance of fatty acids by increasing docosahexaenoic acid and decreasing the levels of arachidonic acid in a lung epithelial cell line and primary leukocytes derived from CF patients. Furthermore, for the first time we also demonstrate the effect of fenretinide on multiple unsaturated fatty acids, as well as differential effects on the levels of long- compared to very-long-chain saturated fatty acids which are important substrates of complex phospholipids. Finally, we demonstrate that pre-treating mice with fenretinide in a chronic model of P. aeruginosa lung infection efficiently decreases the accumulation of mucus. These findings suggest that fenretinide may offer a new approach to therapeutic modulation of pathological mucus production in CF.
Department of Biochemistry McGill University Montreal Quebec Canada
Department of Human Genetics McGill University Montreal Quebec Canada
Department of Medicine Division of Experimental Medicine McGill University Montreal Quebec Canada
Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada
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- $a Cystic fibrosis (CF) is the most common genetic disease in Caucasians. CF is manifested by abnormal accumulation of mucus in the lungs, which serves as fertile ground for the growth of microorganisms leading to recurrent infections and ultimately, lung failure. Mucus in CF patients consists of DNA from dead neutrophils as well as mucins produced by goblet cells. MUC5AC mucin leads to pathological plugging of the airways whereas MUC5B has a protective role against bacterial infection. Therefore, decreasing the level of MUC5AC while maintaining MUC5B intact would in principle be a desirable mucoregulatory treatment outcome. Fenretinide prevented the lipopolysaccharide-induced increase of MUC5AC gene expression, without affecting the level of MUC5B, in a lung goblet cell line. Additionally, fenretinide treatment reversed the pro-inflammatory imbalance of fatty acids by increasing docosahexaenoic acid and decreasing the levels of arachidonic acid in a lung epithelial cell line and primary leukocytes derived from CF patients. Furthermore, for the first time we also demonstrate the effect of fenretinide on multiple unsaturated fatty acids, as well as differential effects on the levels of long- compared to very-long-chain saturated fatty acids which are important substrates of complex phospholipids. Finally, we demonstrate that pre-treating mice with fenretinide in a chronic model of P. aeruginosa lung infection efficiently decreases the accumulation of mucus. These findings suggest that fenretinide may offer a new approach to therapeutic modulation of pathological mucus production in CF.
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