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Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Oct 30:158538. doi: 10.1016/j.bbalip.2019.158538. [Epub ahead of print]

Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction.

Author information

1
Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, Montreal, Quebec, Canada.
2
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
3
Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, Montreal, Quebec, Canada.
4
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, Montreal, Quebec, Canada.
5
Institute of Immunology, Faculty of Medicine, Universidad Central de Venezuela, Bolivarian Republic of Venezuela.
6
Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
7
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
8
Department of Human Genetics, McGill University, Montreal, Quebec, Canada; Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada; Program in Infectious Diseases and Immunity in Global Health, McGill University Health Center, Montreal, Quebec, Canada. Electronic address: danuta.radzioch@mcgill.ca.

Abstract

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.

KEYWORDS:

CFTR; Cystic fibrosis; Mucins; PUFAs

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