Unravelling the role of sphingolipids in cystic fibrosis lung disease

Aureli, Massimo; Schiumarini, Domitilla; Loberto, Nicoletta; Bassi, Rajiv; Tamanini, Anna; Mancini, Giulia; Tironi, Matteo; Munari, Silvia; Cabrini, Giulio; Dechecchi, Maria Cristina; Sonnino, Sandro

doi:10.1016/j.chemphyslip.2016.08.002

Cited by 29 publications

(32 citation statements)

References 88 publications

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“…Sphingolipid dysregulation is a well-known occurrence following insult or injury of any kind to the lung. Elevated levels of ceramide or dysregulation of the ceramide/S1P axis are detected in many pathological conditions, including those observed following radiation insult 67 – 69 . The hydrolysis of sphingomyelin leading to the production of ceramide following injury or stress to the lung is a well characterized pathway; this sphingomyelin cycle is believed to be responsible for the decreases in the detection of these lipids observed here.…”

Section: Resultsmentioning

confidence: 99%

Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI

Carter

Jones

Farese

et al. 2017

Sci Rep

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Radiation-induced lung injury (RILI) is a delayed effect of acute radiation exposure that can limit curative cancer treatment therapies and cause lethality following high-dose whole-thorax lung irradiation (WTLI). To date, the exact mechanisms of injury development following insult remain ill-defined and there are no FDA approved pharmaceutical agents or medical countermeasures. Traditionally, RILI development is considered as three phases, the clinically latent period, the intermediate acute pneumonitis phase and the later fibrotic stage. Utilizing matrix-assisted laser desorption ionization mass spectrometry imaging, we identified a number of lipids that were reflective of disease state or injury. Lipids play central roles in metabolism and cell signaling, and thus reflect the phenotype of the tissue environment, making these molecules pivotal biomarkers in many disease processes. We detected decreases in specific surfactant lipids irrespective of the different pathologies that presented within each sample at 180 days post whole-thorax lung irradiation. We also detected regional increases in ether-linked phospholipids that are the precursors of PAF, and global decreases in lipids that were reflective of severe fibrosis. Taken together our results provide panels of lipids that can differentiate between naïve and irradiated samples, as well as providing potential markers of inflammation and fibrosis.

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Section: Resultsmentioning

confidence: 99%

Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI

Carter

Jones

Farese

et al. 2017

Sci Rep

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“…Several studies in different CF models strongly support the existence of a relationship between SLs, inflammatory response, and susceptibility to bacterial infection. In particular, increased PM Cer levels in CF bronchi seem to be correlated with the proinflammatory status characterizing CF lung disease [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Several factors contribute to the severity of CF inflammation. Among these, an increasing number of studies highlight that sphingolipids (SLs) play an important regulatory role in CF pulmonary infection and inflammation [ 6 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

Evidence for the Involvement of Lipid Rafts and Plasma Membrane Sphingolipid Hydrolases inPseudomonas aeruginosaInfection of Cystic Fibrosis Bronchial Epithelial Cells

Schiumarini

Loberto

Mancini

et al. 2017

Mediators of Inflammation

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Cystic fibrosis (CF) is the most common autosomal genetic recessive disease caused by mutations of gene encoding for the cystic fibrosis transmembrane conductance regulator. Patients with CF display a wide spectrum of symptoms, the most severe being chronic lung infection and inflammation, which lead to onset of cystic fibrosis lung disease. Several studies indicate that sphingolipids play a regulatory role in airway inflammation. The inhibition and downregulation of GBA2, the enzyme catabolizing glucosylceramide to ceramide, are associated with a significant reduction of IL-8 production in CF bronchial epithelial cells. Herein, we demonstrate that GBA2 plays a role in the proinflammatory state characterizing CF cells. We also report for the first time that Pseudomonas aeruginosa infection causes a recruitment of plasma membrane-associated glycosphingolipid hydrolases into lipid rafts of CuFi-1-infected cells. This reorganization of cell membrane may be responsible for activation of a signaling cascade, culminating in aberrant inflammatory response in CF bronchial epithelial cells upon bacterial infection. Taken together, the presented data further support the role of sphingolipids and their metabolic enzymes in controlling the inflammatory response in CF.

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“…Here we found that BSS partly reduces the activation of the PKCα isoform in a completely different model, namely the bronchial epithelial cells challenged with P. aeruginosa ( Figure 7 ), which we found involved with a relevant pro-inflammatory role in the Ca 2+ -dependent signaling machinery, leading to IL-8 gene expression induced by P. aeruginosa in CF bronchial epithelial cells (Bezzerri et al, 2011b). The role of BSS in the organization of lipid rafts of plasma membranes and in the modulation of ceramide (Beck et al, 2007; Hąc-Wydro, 2013; Grosjean et al, 2015) also opens interesting insights in relation to sphingolipid metabolism and inflammation in CF lung disease (for review see Aureli et al, 2016). …”

Section: Discussionmentioning

confidence: 99%

β-Sitosterol Reduces the Expression of Chemotactic Cytokine Genes in Cystic Fibrosis Bronchial Epithelial Cells

et al. 2017

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Extracts from Nigella arvensis L. seeds, which are widely used as anti-inflammatory remedies in traditional medicine of Northern Africa, were able to inhibit the expression of the pro-inflammatory neutrophil chemokine Interleukin (IL)-8 in Cystic Fibrosis (CF) bronchial epithelial IB3-1 cells exposed to the Gram-negative bacterium Pseudomonas aeruginosa. The chemical composition of the extracts led to the identification of three major components, β-sitosterol, stigmasterol, and campesterol, which are the most abundant phytosterols, cholesterol-like molecules, usually found in plants. β-sitosterol (BSS) was the only compound that significantly reproduced the inhibition of the P. aeruginosa-dependent expression of IL-8 at nanomolar concentrations. BSS was tested in CF airway epithelial CuFi-1 cells infected with P. aeruginosa. BSS (100 nM), showed a significant and consistent inhibitory activity on expression of the P. aeruginosa-stimulated expression chemokines IL-8, GRO-α GRO-β, which play a pivotal role in the recruitment of neutrophils in CF inflamed lungs. Preliminary mechanistic analysis showed that BSS partially inhibits the P. aeruginosa-dependent activation of Protein Kinase C isoform alpha, which is known to be involved in the transmembrane signaling activating IL-8 gene expression in bronchial epithelial cells. These data indicate BSS as a promising molecule to control excessive lung inflammation in CF patients.

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Unravelling the role of sphingolipids in cystic fibrosis lung disease

Cited by 29 publications

References 88 publications

Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI

Lipidomic dysregulation within the lung parenchyma following whole-thorax lung irradiation: Markers of injury, inflammation and fibrosis detected by MALDI-MSI

Evidence for the Involvement of Lipid Rafts and Plasma Membrane Sphingolipid Hydrolases inPseudomonas aeruginosaInfection of Cystic Fibrosis Bronchial Epithelial Cells

β-Sitosterol Reduces the Expression of Chemotactic Cytokine Genes in Cystic Fibrosis Bronchial Epithelial Cells

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