Myriocin treatment of CF lung infection and inflammation: complex analyses for enigmatic lipids

Abstract

Purpose. Our aim was to use quantitative and qualitative analyses to gain further insight into the role of ceramide in Cystic Fibrosis (CF). Sphingolipid ceramide is a known inflammatory mediator and its accumulation in inflamed lung has been reported in different types of emphysema, Chronic Obstructive Pulmonary disease and CF. CF is caused by a mutation of the chloride channel and associated with hyper-inflammation of the respiratory airways and high susceptibility to on-going infections. We have previously demonstrated that de novo ceramide synthesis is enhanced in lung inflammation and sustains P. aeruginosa pulmonary infection in a CF murine model. Methods. We used Liquid Chromatography and MALDI Imaging coupled with Mass Spectrometry, Confocal Laser Scan Microscopy and histology analyses to reveal otherwise undecipherable information. Results. We demonstrated that i) up-regulated ceramide synthesis in the alveoli is strictly related to alveolar infection and inflammation; ii) alveolar ceramide (C16) can be specifically targeted by nanocarrier delivery of the ceramide synthesis inhibitor Myriocin (Myr); iii) Myr is able to downmodulate pro-inflammatory lyso-PC, favouring an increase in anti-inflammatory PCs. Conclusions. We concluded that Myr modulates alveolar lipids milieu, reducing hyper-inflammation and favouring anti-microbial effective response in CF mouse model.

Signalling Effects Induced by Acid Ceramidase in Human Epithelial Or Leukemic Cell Lines

“…We and others have previously shown that ceramide accumulates in airway epithelial cells and macrophages from mice and patients with cystic fibrosis [3][4][5][6][7][8][9][10][11][12][13][14][15]. In particular, these studies detected a significant increase of C16, C18 and C20 ceramide species in epithelial cells of the upper airways [7,14,16].…”

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

“…Dyslipidemia has been associated with CF disease, and it is characterized by a reduced absorption and increased synthesis of lipids [ 1 , 2 , 53 , 57 , 58 , 59 , 60 , 61 , 62 ]. Moreover, cholesterol and the inflammatory lipid ceramide have been shown to accumulate in CF peripheral organs, in particular at the airways level [ 4 , 23 , 26 , 63 , 64 , 65 , 66 ]. Although altered lipid metabolism is a common feature of chronic inflammatory diseases, the contribution of lipids in CF pathophysiology is still to be fully elucidated.…”

“…Several studies reported an altered lipid homeostasis in blood and peripheral tissues in CF patients [ 1 , 2 , 20 , 21 , 22 , 23 , 24 ], and demonstrated the pathological role of the inflammatory ceramide accumulation in CF airways [ 4 , 25 ]. In a CF mouse model and in bronchial epithelial cells, our group previously demonstrated that hampering ceramide accumulation by the sphingolipid synthesis inhibitor myriocin (Myr) reduces inflammation and ameliorates the response against microbial infection in vivo and in vitro by promoting cell-killing ability [ 8 , 25 , 26 ]. Moreover, the inhibition of ceramide synthesis in CF cells activates TFEB, a master regulator of the stress response.…”

Long and Very-Long-Chain Ceramides Correlate with A More Aggressive Behavior in Skull Base Chordoma Patients

“…The involvement of de-novo ceramide synthesis has been shown in different immunometabolic diseases clusters such as obesity, diabetes and neurodegeneration, cystic fibrosis, and retinitis pigmentosa [51,52,53,54,55]. Several recent studies showed that intra-tracheal administration of Myr in CF mouse model infected with Pseudomonas aeruginosa or Aspergillus fumigatus showed an anti-inflammatory role due to the inhibition of de-novo sphingolipid synthesis [54,56,57,58]. Therefore, Myr may have a significant role in the future therapeutic innovation and application in chordoma patients where a de-novo ceramide synthesis seems to be over activated.…”