Modulators of Sphingolipid Metabolism Reduce Lung Inflammation

作者：Maria Cristina Dechecchi, Elena Nicolis, Paola Mazzi, Federica Cioffi, Valentino Bezzerri, Ilaria Lampronti, Song Huang, Ludovic Wiszniewski, Roberto Gambari, Maria Teresa Scupoli, Giorgio Berton, Giulio Cabrini · 发表于：American Journal of Respiratory Cell and Molecular Biology · 年份：2011 · DOI：10.1165/rcmb.2010-0457oc · 被引用次数：47 · 研究领域：Sphingolipid Metabolism and Signaling、Lipid Membrane Structure and Behavior、Inflammasome and immune disorders

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 on...