title: Inhibition of ceramide de novo synthesis by myriocin produces the double effect of reducing pathological inflammation and exerting antifungal activity against A. fumigatus airways infection.
abstract: BACKGROUND
  Fungal infections develop in pulmonary chronic inflammatory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD) and Cystic Fibrosis (CF). The available antifungal drugs may fail to eradicate fungal pathogens, that can invade the lungs and vessels and spread by systemic circulation taking advantage of defective lung immunity. An increased rate of sphingolipid de novo synthesis, leading to ceramide accumulation, was demonstrated in CF and COPD inflamed lungs. The inhibitor of sphingolipid synthesis myriocin reduces inflammation and ameliorates the response against bacterial airway infection in CF mice. Myriocin also inhibits sphingolipid synthesis in fungi and exerts a powerful fungistatic effect.
  
  
  METHODS
  We treated Aspergillus fumigatus infected airway epithelial cells with myriocin and we administered myriocin-loaded nanocarriers to A. fumigatus infected mice lung.
  
  
  RESULTS
  We demonstrate here that de novo synthesized ceramide mediates the inflammatory response induced by A. fumigatus infection in airway epithelia. CF epithelial cells are chronically inflamed and defective in killing internalized conidia. Myriocin treatment reduced ceramide increase and inflammatory mediator release whereas it upregulated HO1 and NOD2, allowing the recovery of a functional killing of conidia in these cells. Myriocin-loaded nanocarriers, intratracheally administered to mice, significantly reduced both the inflammatory response induced by A. fumigatus pulmonary challenge and fungal lung invasion.
  
  
  CONCLUSIONS
  We conclude that inhibition of sphingolipid synthesis can be envisaged as a dual anti-inflammatory and anti-fungal therapy in patients suffering from chronic lung inflammation with compromised immunity.
  
  
  CONCLUSIONS
  Myriocin represents a powerful agent for inflammatory diseases and fungal infection.
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caretti
authors.affiliation: Institute of Microbiology, Cattolica del Sacro Cuore University, Rome, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Torelli
authors.affiliation: Microbiology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perdoni
authors.affiliation: Pathology Division, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Falleni
authors.affiliation: Pathology Division, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Delfina
authors.initials: D
authors.lastname: Tosi
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Aida
authors.initials: A
authors.lastname: Zulueta
authors.affiliation: Research Unit on BioActive Molecules, Department of Biomedicinal Chemistry, IQAC-CSIC, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.affiliation: Institute of Microbiology, Cattolica del Sacro Cuore University, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ghidoni
authors.affiliation: Microbiology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Borghi
authors.affiliation: Biochemistry and Molecular Biology Laboratory, Health Sciences Department, University of Milan, San Paolo Hospital Medical School, Milan, Italy. Electronic address: paola.signorelli@unimi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Signorelli
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001232:Aspergillus fumigatus; D002460:Cell Line; D002518:Ceramides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055732:Pulmonary Aspergillosis / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000893:Anti-Inflammatory Agents; D000935:Antifungal Agents; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; C001996:thermozymocidin
keywords: Ceramide; Chronic inflammation; Cystic Fibrosis; Fungi; Infection; Lung; Myriocin; Nanocarriers