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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Facchini, Marcella De Fino, Ida Signorelli, Paola Riva, Camilla Caretti, Anna Bragonzi, Alessandra Casas, Josefina Ghidoni, Riccardo Gasco, Paolo Fabriàs, Gemma Musicanti, Claudia |
| Description | Author Affiliation: Caretti A ( Department of Health Sciences, University of Milan, San Paolo Hospital, Italy.) |
| Abstract | BACKGROUND: Sphingolipids take part in immune response and can initiate and/or sustain inflammation. Various inflammatory diseases have been associated with increased ceramide content, and pharmacological reduction of ceramide diminishes inflammation damage in vivo. Inflammation and susceptibility to microbial infection are two elements in a vicious circle. Recently, sphingolipid metabolism inhibitors were used to reduce infection. Cystic fibrosis (CF) is characterized by a hyper-inflammation and an excessive innate immune response, which fails to evolve into adaptive immunity and to eradicate infection. Chronic infections result in lung damage and patient morbidity. Notably, ceramide content in mucosa airways is higher in CF mouse models and in patients than in control mice or healthy subjects. METHODS: The therapeutic potential of myriocin, an inhibitor of the sphingolipid de novo synthesis rate limiting enzyme (Serine Palmitoyl Transferase, SPT),was investigated in CF cells and mice models. RESULTS: We treated CF human respiratory epithelial cells with myriocin, This treatment resulted in reduced basal, as well as TNF -stimulated, inflammation. In turn, TNF induced an increase in SPT in these cells, linking de novo synthesis of ceramide to inflammation. Furthermore, myriocin-loaded nanocarrier, injected intratrachea prior to P. aeruginosa challenge, enabled a significant reduction of lung infection and reduced inflammation. CONCLUSIONS: The presented data suggest that de novo ceramide synthesis is constitutively enhanced in CF mucosa and that it can be envisaged as pharmacological target for modulating inflammation and restoring effective innate immunity against acute infection. GENERAL SIGNIFICANCE: Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 1 |
| Volume Number | 1840 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2014-01-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Anti-Inflammatory Agents Pharmacology Antifungal Agents Cell Proliferation Drug Effects Cystic Fibrosis Drug Therapy Fatty Acids, Monounsaturated Nanoparticles Chemistry Sphingolipids Animals Administration & Dosage Blotting, Western Ceramides Metabolism Chromatography, Liquid Complications Immunology Drug Carriers Enzyme-Linked Immunosorbent Assay Interleukin-6 Genetics Interleukin-8 Mice Mice, Inbred CFTR Pseudomonas Infections Etiology Pseudomonas Aeruginosa Pathogenicity RNA, Messenger Real-Time Polymerase Chain Reaction Respiratory Mucosa Respiratory Tract Infections Reverse Transcriptase Polymerase Chain Reaction Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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