Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis.

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 TNFα-stimulated, inflammation. In turn, TNFα 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.

• Authors: Anna Caretti, Alessandra Bragonzi, Marcella Facchini, Ida De Fino, Camilla Riva, Paolo Gasco, Claudia Musicanti, Josefina Casas, Gemma Fabriàs, Riccardo Ghidoni, Paola Signorelli
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1840 Issue 1 Pg. 586-94 (Jan 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24141140 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Antifungal Agents
• Ceramides
• Drug Carriers
• Fatty Acids, Monounsaturated
• Interleukin-6
• Interleukin-8
• RNA, Messenger
• Sphingolipids
• thermozymocidin

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacology)
• Antifungal Agents (administration & dosage, pharmacology)
• Blotting, Western
• Cell Proliferation (drug effects)
• Ceramides (metabolism)
• Chromatography, Liquid
• Cystic Fibrosis (complications, drug therapy, immunology)
• Drug Carriers
• Enzyme-Linked Immunosorbent Assay
• Fatty Acids, Monounsaturated (administration & dosage, pharmacology)
• Female
• Humans
• Interleukin-6 (genetics, metabolism)
• Interleukin-8 (genetics, metabolism)
• Male
• Mice
• Mice, Inbred CFTR
• Nanoparticles (administration & dosage, chemistry)
• Pseudomonas Infections (drug therapy, etiology)
• Pseudomonas aeruginosa (drug effects, pathogenicity)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Respiratory Mucosa (drug effects, immunology, metabolism)
• Respiratory Tract Infections (drug therapy, etiology)
• Reverse Transcriptase Polymerase Chain Reaction
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Sphingolipids (chemistry)