title: Modulators of sphingolipid metabolism reduce lung inflammation.
abstract: The investigation of novel targets for the treatment of cystic fibrosis (CF) lung inflammation is a major priority, considering that no effective therapy is available for this purpose. Consistent with the evidence that the sphingolipid (SL) ceramide regulates airway inflammation and infection in mice and patients with CF, SLs were identified as targets for treating pulmonary disorders, including CF. Because miglustat, an inhibitor of the synthesis of glycosphingolipids, reduces the Pseudomonas aeruginosa-dependent transcription of the IL-8 gene in bronchial cells, we examined the effects of miglustat and amitriptyline, another drug affecting ceramide metabolism, on the expression of 92 genes implicated in host immune defense. Infection with the P. aeruginosa strain PAO1 up-modulated the expression of 14 (27%) genes in IB3-1 cells and 15 (29%) genes in CF primary respiratory epithelia grown at an air-liquid interface, including chemokines (IL-8, growth-regulated Gro-α/β/γ proteins, and granulocyte chemotactic peptide-2 [GCP-2]), proinflammatory cytokines (IL-1α/β, IL-6, and TNF-α), and the intercellular adhesion molecule-1, nuclear factor kB1, toll like receptor 2, and human defensin B4 genes, confirming that bronchial epithelium is an important source of inflammatory mediators. Both miglustat and amitriptyline reduced the immune response, an effect that paralleled a decrease in the P. aeruginosa-induced accumulation of ceramide. Miglustat (100 mg/kg), given to C57BL/6 mice once daily for a period of 3 consecutive days before lipopolysaccharide (LPS) challenge, strongly reduced the number of neutrophils recruited in the airways and the expression of the keratinocyte-derived chemokine in lung extracts. Collectively, these results indicate that targeting the metabolism of SLs can down-modulate the recruitment of neutrophils into the lung.
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Piazzale Stefani 1, 37126 Verona, Italy. cristina.dechecchi@ospedaleuniverona.it
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Dechecchi
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolis
authors.forename: Paola
authors.initials: P
authors.lastname: Mazzi
authors.forename: Federica
authors.initials: F
authors.lastname: Cioffi
authors.forename: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.forename: Song
authors.initials: S
authors.lastname: Huang
authors.forename: Ludovic
authors.initials: L
authors.lastname: Wiszniewski
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Scupoli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005786:Gene Expression Regulation / Q000187:drug effects; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000472:pathogenicity; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; D002518:Ceramides; D018836:Inflammation Mediators; D016209:Interleukin-8; D008070:Lipopolysaccharides; C440499:lipopolysaccharide, Escherichia coli O111 B4; D000639:Amitriptyline; D017485:1-Deoxynojirimycin; C059896:miglustat