Ceramide Is Increased in the Lower Airway Epithelium of People with Advanced Cystic Fibrosis Lung Disease

Brodlie, Malcolm; McKean, Michael C; Johnson, Gail; Gray, Joe W.; Fisher, Andrew J.; Corris, Paul A.; Lordan, James; Ward, Chris

doi:10.1164/rccm.200905-0799oc

Cited by 91 publications

(89 citation statements)

References 39 publications

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“…A study using biochemical techniques, fluorescence microscopy, and mass spectrometry demonstrated that CFTR deficiency results in the accumulation of ceramide in bronchial, tracheal, and intestinal epithelial cells, in alveolar macrophages in cystic fibrosis mice, and in nasal epithelial cells from cystic fibrosis patients (Teichgräber et al, 2008;Zhang et al, 2009;Becker et al, 2010a,b) (Figure 1). The accumulation of ceramide in lung tissues and cells from cystic fibrosis patients or mice has been confirmed by several studies using human transplant material, mouse lung tissue, and cultured cells (Brodlie et al, 2010;Ulrich et al, 2010;Bodas et al, 2011a,b;Caretti et al, 2014;Itokazu et al, 2014). Brodlie et al (2010) provided detailed mass spectrometry data about the accumulation of various ceramide species in the lung and demonstrated the substantial accumulation of the ceramide species C16, C18, and C20 in the lungs of cystic fibrosis patients.…”

Section: Ceramide In Cystic Fibrosismentioning

confidence: 88%

“…The accumulation of ceramide in lung tissues and cells from cystic fibrosis patients or mice has been confirmed by several studies using human transplant material, mouse lung tissue, and cultured cells (Brodlie et al, 2010;Ulrich et al, 2010;Bodas et al, 2011a,b;Caretti et al, 2014;Itokazu et al, 2014). Brodlie et al (2010) provided detailed mass spectrometry data about the accumulation of various ceramide species in the lung and demonstrated the substantial accumulation of the ceramide species C16, C18, and C20 in the lungs of cystic fibrosis patients. However, at present it is unknown whether distinct ceramide species in the lung are associated with specific pathophysiological changes in CF patients.…”

Section: Ceramide In Cystic Fibrosismentioning

confidence: 88%

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Ceramide and sphingosine in pulmonary infections

Seitz

Grassmé

Edwards

et al. 2015

Biological Chemistry

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Acid sphingomyelinase and ceramide have previously been shown to play a central role in infections with Neisseria gonorrhoeae, Staphylococcus aureus, Listeria monocytogenes, Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, and Mycobacterium avium. Recent studies have extended the role of sphingolipids in bacterial infections and have demonstrated that ceramide and sphingosine are central to the defense of lungs against bacterial pathogens. Ceramide accumulates in the airway epithelium of cystic fibrosis and ceramide synthase 2 (CerS2)-deficient mice, which respond to the lack of very long chain (C22-C24-) ceramides with a profound compensatory increase of long chain (mainly C16-) ceramides. In contrast, sphingosine is present in healthy airways and is almost completely absent from diseased or deficient epithelial cells. Both sphingolipids are crucially involved in the high susceptibility to infection of cystic fibrosis and CerS2-deficient mice, as indicated by findings showing that the normalization of ceramide and sphingosine levels rescue these mice from acute infection with P. aeruginosa.

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Section: Ceramide In Cystic Fibrosismentioning

confidence: 88%

Section: Ceramide In Cystic Fibrosismentioning

confidence: 88%

Ceramide and sphingosine in pulmonary infections

Seitz

Grassmé

Edwards

et al. 2015

Biological Chemistry

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“…10,31,32 Furthermore, it has been reported that CERs are important regulators of tumor cell death following exposure to stress stimuli 33,34 and changes in sphingolipid metabolism impact on pancreatic b-cell function. 35 Our in vivo and in vitro findings of CERs and cell death are in agreement with these previous observations.…”

Section: Discussionmentioning

confidence: 99%

Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia

Melland-Smith

Ermini²,

Chauvin³

et al. 2015

Autophagy

125

162

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transcription factor 4, p107/p130-binding; HIF1A, hypoxia inducible factor 1, a, subunit (basic helix-loophelix transcription factor); LC-MS/MS, liquid chromatography-tandem mass spectrometry; LAMP1, lysosomal-associated membrane protein 1; LC3B-II, cleaved and lipidated form of microtubule-associated protein 1 light chain 3 b (MAP1LC3B/LC3B); MALDI-MS, matrix-assisted laser desorption/ionization-mass spectrometry; MCL1, myeloid cell leukemia 1; PE, preeclampsia; PTC, preterm control; S1P, sphingosine-1-phosphate; Sa, sphinganine; siRNA, small-interfering ribonucleic acid; SQSTM1/p62, sequestosome 1; SM, sphingomyelin; SMPD1, sphingomyelin phosphodiesterase 1, acid lysosomal (acid sphingomyelinase); SNP, sodium nitroprusside (III); SPH, sphingosine; SPT, serine palmitoyltransferase; ST, syncytium/syncytiotrophoblast cells; TC, term control; TGFB, transforming growth factor b.Bioactive sphingolipids including ceramides are involved in a variety of pathophysiological processes by regulating cell death and survival. The objective of the current study was to examine ceramide metabolism in preeclampsia, a serious disorder of pregnancy characterized by oxidative stress, and increased trophoblast cell death and autophagy. Maternal circulating and placental ceramide levels quantified by tandem mass spectrometry were elevated in pregnancies complicated by preeclampsia. Placental ceramides were elevated due to greater de novo synthesis via high serine palmitoyltransferase activity and reduced lysosomal breakdown via diminished ASAH1 expression caused by TGFB3-induced E2F4 transcriptional repression. SMPD1 activity was reduced; hence, sphingomyelin degradation by SMPD1 did not contribute to elevated ceramide levels in preeclampsia. Oxidative stress triggered similar changes in ceramide levels and acid hydrolase expression in villous explants and trophoblast cells. MALDI-imaging mass spectrometry localized the ceramide increases to the trophophoblast layers and syncytial knots of placentae from pregnancies complicated by preeclampsia. ASAH1 inhibition or ceramide treatment induced autophagy in human trophoblast cells via a shift of the BOK-MCL1 rheostat toward prodeath BOK. Pharmacological inhibition of ASAH1 activity in pregnant mice resulted in increased placental ceramide content, abnormal placentation, reduced fetal growth, and increased autophagy via a similar shift in the BOK-MCL1 system. Our results reveal that oxidative stressinduced reduction of lysosomal hydrolase activities in combination with elevated de novo synthesis leads to ceramide overload, resulting in increased trophoblast cell autophagy, and typifies preeclampsia as a sphingolipid storage disorder.

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“…Recent animal studies offer an attractive novel possibility to treat cystic fibrosis [9]: We demonstrated in mice genetically deficient for Cftr an accumulation of ceramide in tracheal and bronchial epithelial cells [9]. The results were recently independently confirmed and transferred to the human situation demonstrating accumulation of ceramide in bronchial epithelial cells of patients with cystic fibrosis [9,10,11,12]. Ceramide mediates increased death of bronchial epithelial cells resulting in a release of dead cells and finally DNA into the bronchial lumen [9].…”

Section: Introductionmentioning

confidence: 99%

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

Naehrlich

Mainz

Adams

et al. 2013

Cell Physiol Biochem

1,958

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Background/Aims: Several recent studies revealed an accumulation of ceramide in bronchial, tracheal and intestinal epithelial cells of mice and patients with cystic fibrosis (CF). Normalization of ceramide concentrations in lungs of CF mice employing the functional acid sphingomyelinase inhibitor amitriptyline also normalized mucociliary clearance, chronic inflammation and infection susceptibility to pulmonary P. aeruginosa in these mice. Methods: To test for a beneficial effect of amitriptyline in vivo, we performed a phase IIb randomised, double-blind, placebo-controlled study. Twenty-one CF patients were treated with 25 mg/d amitriptyline twice daily for 28 days. The placebo consisted of 19 patients and was also treated twice per day. The primary endpoint was the change in lung function in the intention-to-treat (ITT) population. Secondary endpoints were ceramide levels in epithelial cells and safety. Results: After treatment, forced expiratory volume in 1 sec predicted (FEV₁) increased 6.3±11.5% (p=0.08) in the ITT population (36 of 40 CF patients) and 8.5±10% (p=0.013) in the per protocol (PP) population (29 of 40 patients). Ceramide levels decreased in nasal epithelial cells after amitriptyline treatment. Amitriptyline had no severe and only mild and mostly transient adverse effects, i.e. xerostomia and tiredness. Conclusion: Amitriptyline is safe in CF-patients, increases FEV₁ and reduces ceramide in lung cells of CF patients.

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Ceramide Is Increased in the Lower Airway Epithelium of People with Advanced Cystic Fibrosis Lung Disease

Abstract: Immunoreactive ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis. Detected by mass-spectrometry ceramide species C16:0, C18:0, and C20:0 but not C22:0 are increased.

Cited by 91 publications

References 39 publications

Ceramide and sphingosine in pulmonary infections

Ceramide and sphingosine in pulmonary infections

Disruption of sphingolipid metabolism augments ceramide-induced autophagy in preeclampsia

Therapy of CF-Patients with Amitriptyline and Placebo - a Randomised, Double-Blind, Placebo-Controlled Phase IIb Multicenter, Cohort-Study

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