Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis
| Autor: | Vinciane Saint-Criq, Alexandra Trigg, John P. Clancy, Malcolm Brodlie, Andrew J. Fisher, A. John Simpson, John Gallagher, Michael A. Gray, Albert Koulman, Emily Mavin, Elizabeth L. Kramer, Melissa J. McDonnell, Aaron Gardner, Edward H. Schuchman, Bernard Verdon, Chris Ward, Iram J. Haq, Erich Gulbins, Katrin Anne Becker |
|---|---|
| Přispěvatelé: | Institute for Cell and Molecular Biosciences, Newcastle University [Newcastle], Koulman, Albert [0000-0001-9998-051X], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Pulmonary and Respiratory Medicine
Ceramide [SDV]Life Sciences [q-bio] Medizin Inflammation Critical Care and Intensive Care Medicine Cystic fibrosis Sphingolipid law.invention 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sphingosine law medicine 030212 general & internal medicine Lung business.industry medicine.disease 3. Good health Acid Ceramidase medicine.anatomical_structure 030228 respiratory system chemistry Recombinant DNA Cancer research medicine.symptom business |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, 2020, 202 (8), pp.1133-1145. ⟨10.1164/rccm.202001-0180OC⟩ |
| ISSN: | 1073-449X 1535-4970 |
| DOI: | 10.1164/rccm.202001-0180OC⟩ |
| Popis: | Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully-differentiated cultures of primary human airway epithelial cells and co-cultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting and quantitative polymerase chain reaction were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium due to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to Pseudomonas aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in the apical membrane of cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|