Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction
| Autor: | Basil J. Petrof, Dušan Garić, John W. Hanrahan, Francisek Kopriva, Marian Hajduch, Juhi Shah, Daciana Catalina Dumut, Mina Youssef, Danuta Radzioch, Maria Johanna Peña, Juan B. De Sanctis |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cystic Fibrosis Docosahexaenoic Acids Fenretinide Administration Oral Respiratory Mucosa Mucin 5AC Cell Line Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Internal medicine medicine Animals Humans Mice Inbred CFTR Pseudomonas Infections Lung Molecular Biology Phospholipids chemistry.chemical_classification Goblet cell Arachidonic Acid Chemistry Mucin Fatty acid Pneumonia Cell Biology respiratory system Mucin-5B Mucus Rats 3. Good health Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure 030228 respiratory system Docosahexaenoic acid Pseudomonas aeruginosa Arachidonic acid Polyunsaturated fatty acid |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1865:158538 |
| ISSN: | 1388-1981 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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