Dirk Westhölter1, Fabian Schumacher2, Nuria Wülfinghoff3, Sivagurunathan Sutharsan4, Svenja Strassburg4, Burkhard Kleuser2, Peter A Horn5, Sebastian Reuter3, Erich Gulbins6, Christian Taube3, Matthias Welsner4. 1. Department of Pulmonary Medicine, University Hospital Essen- Ruhrlandklinik, Tüschener Weg 40, Essen 45239, Germany. Electronic address: dirk.westhoelter@uk-essen.de. 2. Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany. 3. Department of Pulmonary Medicine, University Hospital Essen- Ruhrlandklinik, Tüschener Weg 40, Essen 45239, Germany. 4. Adult Cystic Fibrosis Center, Department of Pulmonary Medicine, University Hospital Essen -Ruhrlandklinik, Essen, Germany. 5. Institute for Transfusion Medicine, University of Duisburg-Essen, Essen, Germany. 6. Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH, United States.
Abstract
BACKGROUND: Sphingolipids, in particular ceramides, play an important role in the pathogenesis of cystic fibrosis (CF) lung disease. Ceramides seem to be dysregulated in people with CF (PWCF): An elevated ratio of ceramides C16Cer/ C24Cer has been linked to inflammation and disease severity. CFTR modulators might influence sphingolipid dysregulation in PWCF. METHODS: Sphingolipid profiles were retrospectively analyzed in serum from 112 PWCF and 96 healthy controls as well as in plasma from 25 PWCF before and after treatment with the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid data were correlated with clinical parameters. RESULTS: There were significantly higher levels of long-chain ceramides C18Cer and C20Cer and of the very long-chain ceramide C24:1Cer in PWCF versus healthy controls. Sphingosine levels were significantly reduced and accurately distinguished PWCF from healthy controls. Treatment with ELX/TEZ/IVA was associated with a decrease in levels of long-chain ceramides C16Cer, C18Cer and C20Cer and very long-chain ceramide C24:1Cer. Plasma levels of the most abundant very long-chain ceramide C24Cer as well as sphingosine-1-phosphate increased. Consequently, the ratio of ceramides C16Cer/ C24Cer decreased. Sphingolipid levels showed weak correlations with clinical parameters. CONCLUSIONS: These findings highlight the existence of a distinctive sphingolipid profile in blood from PWCF, which appears to be altered by ELX/TEZ/IVA therapy. Thus, strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies.
BACKGROUND: Sphingolipids, in particular ceramides, play an important role in the pathogenesis of cystic fibrosis (CF) lung disease. Ceramides seem to be dysregulated in people with CF (PWCF): An elevated ratio of ceramides C16Cer/ C24Cer has been linked to inflammation and disease severity. CFTR modulators might influence sphingolipid dysregulation in PWCF. METHODS: Sphingolipid profiles were retrospectively analyzed in serum from 112 PWCF and 96 healthy controls as well as in plasma from 25 PWCF before and after treatment with the CFTR modulator elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Lipid data were correlated with clinical parameters. RESULTS: There were significantly higher levels of long-chain ceramides C18Cer and C20Cer and of the very long-chain ceramide C24:1Cer in PWCF versus healthy controls. Sphingosine levels were significantly reduced and accurately distinguished PWCF from healthy controls. Treatment with ELX/TEZ/IVA was associated with a decrease in levels of long-chain ceramides C16Cer, C18Cer and C20Cer and very long-chain ceramide C24:1Cer. Plasma levels of the most abundant very long-chain ceramide C24Cer as well as sphingosine-1-phosphate increased. Consequently, the ratio of ceramides C16Cer/ C24Cer decreased. Sphingolipid levels showed weak correlations with clinical parameters. CONCLUSIONS: These findings highlight the existence of a distinctive sphingolipid profile in blood from PWCF, which appears to be altered by ELX/TEZ/IVA therapy. Thus, strategies for sphingolipid remodeling need to be reassessed and adjusted in the light of highly effective CFTR modulator therapies.
Authors: Amanda Centorame; Daciana Catalina Dumut; Mina Youssef; Martin Ondra; Irenej Kianicka; Juhi Shah; Radu Alexandru Paun; Tomas Ozdian; John W Hanrahan; Ekaterina Gusev; Basil Petrof; Marian Hajduch; Radu Pislariu; Juan Bautista De Sanctis; Danuta Radzioch Journal: Front Pharmacol Date: 2022-05-20 Impact factor: 5.988