title: 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.
  
  
  CONCLUSIONS
  Myriocin stands as a powerful immunomodulatory agent for inflammatory and infectious diseases.
authors.affiliation: Department of Health Sciences, University of Milan, San Paolo Hospital, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caretti
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bragonzi
authors.forename: Marcella
authors.initials: M
authors.lastname: Facchini
authors.forename: Ida
authors.initials: I
authors.lastname: De Fino
authors.forename: Camilla
authors.initials: C
authors.lastname: Riva
authors.forename: Paolo
authors.initials: P
authors.lastname: Gasco
authors.forename: Claudia
authors.initials: C
authors.lastname: Musicanti
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D002518:Ceramides / Q000378:metabolism; D002853:Chromatography, Liquid; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018181:Mice, Inbred CFTR; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000209:etiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000188:drug therapy / Q000209:etiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013107:Sphingolipids / Q000737:chemistry*
chemical_list: D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D002518:Ceramides; D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D013107:Sphingolipids; C001996:thermozymocidin
keywords: Ceramide; Cystic fibrosis; Inflammation; Innate immune responses; Nanocarriers; Sphingolipids