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Sphingolipids as targets for inhalation treatment of cystic fibrosis

Lookup NU author(s): Dr Aaron Ions Gardner, Dr Malcolm Brodlie

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Abstract

© 2018 Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of β1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of β1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation.


Publication metadata

Author(s): Becker KA, Riethmuller J, Seitz AP, Gardner A, Boudreau R, Kamler M, Kleuser B, Schuchman E, Caldwell CC, Edwards MJ, Grassme H, Brodlie M, Gulbins E

Publication type: Article

Publication status: Published

Journal: Advanced Drug Delivery Reviews

Year: 2018

Volume: 133

Pages: 66-75

Print publication date: 01/08/2018

Online publication date: 24/04/2018

Acceptance date: 18/04/2018

ISSN (print): 0169-409X

ISSN (electronic): 1872-8294

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.addr.2018.04.015

DOI: 10.1016/j.addr.2018.04.015


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