{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T20:56:57Z","timestamp":1773694617580,"version":"3.50.1"},"reference-count":81,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004063","name":"Knut and Alice Wallenberg Foundation","doi-asserted-by":"publisher","award":["F 2015\/2112"],"award-info":[{"award-number":["F 2015\/2112"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2017-01243"],"award-info":[{"award-number":["2017-01243"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003173","name":"Crafoord Foundation","doi-asserted-by":"publisher","award":["FU"],"award-info":[{"award-number":["FU"]}],"id":[{"id":"10.13039\/501100003173","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Royal Physiografic society of Lund","award":["FU"],"award-info":[{"award-number":["FU"]}]},{"DOI":"10.13039\/100007435","name":"\u00c5ke Wibergs Stiftelse","doi-asserted-by":"publisher","award":["M19-0380"],"award-info":[{"award-number":["M19-0380"]}],"id":[{"id":"10.13039\/100007435","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NMMP 2021","award":["V2021-2102"],"award-info":[{"award-number":["V2021-2102"]}]},{"DOI":"10.13039\/501100001728","name":"Swedish Foundation for International Cooperation in Research and Higher Education","doi-asserted-by":"publisher","award":["MG19-8469"],"award-info":[{"award-number":["MG19-8469"]}],"id":[{"id":"10.13039\/501100001728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Heart failure (HF) is among the main causes of death worldwide. Alterations of sphingosine-1-phosphate (S1P) signaling have been linked to HF as well as to target organ damage that is often associated with HF. S1P\u2019s availability is controlled by the cystic fibrosis transmembrane regulator (CFTR), which acts as a critical bottleneck for intracellular S1P degradation. HF induces CFTR downregulation in cells, tissues and organs, including the lung. Whether CFTR alterations during HF also affect systemic and tissue-specific S1P concentrations has not been investigated. Here, we set out to study the relationship between S1P and CFTR expression in the HF lung. Mice with HF, induced by myocardial infarction, were treated with the CFTR corrector compound C18 starting ten weeks post-myocardial infarction for two consecutive weeks. CFTR expression, S1P concentrations, and immune cell frequencies were determined in vehicle- and C18-treated HF mice and sham controls using Western blotting, flow cytometry, mass spectrometry, and qPCR. HF led to decreased pulmonary CFTR expression, which was accompanied by elevated S1P concentrations and a pro-inflammatory state in the lungs. Systemically, HF associated with higher S1P plasma levels compared to sham-operated controls and presented with higher S1P receptor 1-positive immune cells in the spleen. CFTR correction with C18 attenuated the HF-associated alterations in pulmonary CFTR expression and, hence, led to lower pulmonary S1P levels, which was accompanied by reduced lung inflammation. Collectively, these data suggest an important role for the CFTR-S1P axis in HF-mediated systemic and pulmonary inflammation.<\/jats:p>","DOI":"10.3390\/ijms23020866","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T03:14:03Z","timestamp":1642130043000},"page":"866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Therapeutic CFTR Correction Normalizes Systemic and Lung-Specific S1P Level Alterations Associated with Heart Failure"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0641-4162","authenticated-orcid":false,"given":"Franziska E.","family":"Uhl","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden"},{"name":"Wallenberg Centre for Molecular Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4864-1347","authenticated-orcid":false,"given":"Lotte","family":"Vanherle","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden"},{"name":"Wallenberg Centre for Molecular Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5115-8831","authenticated-orcid":false,"given":"Frank","family":"Matthes","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden"},{"name":"Wallenberg Centre for Molecular Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0793-7213","authenticated-orcid":false,"given":"Anja","family":"Meissner","sequence":"additional","affiliation":[{"name":"Department of Experimental Medical Sciences, Lund University, 221 84 Lund, Sweden"},{"name":"Wallenberg Centre for Molecular Medicine, Lund University, 221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nrd3248","article-title":"Fingolimod (FTY720): Discovery and development of an oral drug to treat multiple sclerosis","volume":"9","author":"Brinkmann","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12905","DOI":"10.1038\/s41598-017-13376-2","article-title":"S1P1 deletion differentially affects TH17 and Regulatory T cells","volume":"7","author":"Eken","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1126\/science.1139221","article-title":"Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate","volume":"316","author":"Pappu","year":"2007","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/nri2400","article-title":"The alliance of sphingosine-1-phosphate and its receptors in immunity","volume":"8","author":"Rivera","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature02284","article-title":"Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1","volume":"427","author":"Matloubian","year":"2004","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1161\/CIRCRESAHA.110.226464","article-title":"Sphingosine-1-phosphate-dependent activation of p38 MAPK maintains elevated peripheral resistance in heart failure through increased myogenic vasoconstriction","volume":"107","author":"Hoefer","year":"2010","journal-title":"Circ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1161\/HYPERTENSIONAHA.117.09088","article-title":"S1PR1 (Sphingosine-1-Phosphate Receptor 1) Signaling Regulates Blood Flow and Pressure","volume":"70","author":"Cantalupo","year":"2017","journal-title":"Hypertension"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1161\/CIRCULATIONAHA.111.039644","article-title":"Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-alpha-dependent activation of sphingosine-1-phosphate signaling","volume":"126","author":"Yang","year":"2012","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/cvr\/cvw256","article-title":"Sphingosine-1-phosphate signalling-a key player in the pathogenesis of Angiotensin II-induced hypertension","volume":"113","author":"Meissner","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1161\/STROKEAHA.114.006365","article-title":"Therapeutically Targeting Tumor Necrosis Factor-alpha\/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage","volume":"46","author":"Yagi","year":"2015","journal-title":"Stroke"},{"key":"ref_11","first-page":"940","article-title":"CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage","volume":"4","author":"Lidington","year":"2019","journal-title":"JACC Basic Trans. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1194\/jlr.RA119000277","article-title":"Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice","volume":"60","author":"Obinata","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8309","DOI":"10.1038\/s41598-019-44845-5","article-title":"Role of the S1P pathway and inhibition by fingolimod in preventing hemorrhagic transformation after stroke","volume":"9","author":"Gallizioli","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Don-Doncow, N., Vanherle, L., Zhang, Y., and Meissner, A. (2019). T-Cell Accumulation in the Hypertensive Brain: A Role for Sphingosine-1-Phosphate-Mediated Chemotaxis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030537"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"44131","DOI":"10.1038\/srep44131","article-title":"Vascular transcriptome profiling identifies Sphingosine kinase 1 as a modulator of angiotensin II-induced vascular dysfunction","volume":"7","author":"Siedlinski","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.molmed.2017.07.001","article-title":"Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?","volume":"23","author":"Pyne","year":"2017","journal-title":"Trends Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Bot, M., Van Veldhoven, P.P., de Jager, S.C., Johnson, J., Nijstad, N., Van Santbrink, P.J., Westra, M.M., Van Der Hoeven, G., Gijbels, M.J., and Muller-Tidow, C. (2013). Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063360"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"16","DOI":"10.5551\/jat.RV17010","article-title":"Sphingosine 1-Phosphate and Atherosclerosis","volume":"25","author":"Kurano","year":"2018","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.yjmcc.2017.07.004","article-title":"Plasma sphingosine-1-phosphate concentrations are associated with systolic heart failure in patients with ischemic heart disease","volume":"110","author":"Polzin","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1161\/HYPERTENSIONAHA.120.17379","article-title":"Plasma S1P (Sphingosine-1-Phosphate) Links to Hypertension and Biomarkers of Inflammation and Cardiovascular Disease: Findings From a Translational Investigation","volume":"78","author":"Jujic","year":"2021","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"985","DOI":"10.3389\/fneur.2020.00985","article-title":"Serum Sphingosine 1-Phosphate (S1P): A Novel Diagnostic Biomarker in Early Acute Ischemic Stroke","volume":"11","author":"Liu","year":"2020","journal-title":"Front. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1161\/ATVBAHA.116.305675","article-title":"Sphingolipids Contribute to Human Atherosclerotic Plaque Inflammation","volume":"36","author":"Edsfeldt","year":"2016","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"H599","DOI":"10.1152\/ajpheart.00314.2021","article-title":"Sphingosine-1-phosphate interactions in the spleen and heart reflect extent of cardiac repair in mice and failing human hearts","volume":"321","author":"Gowda","year":"2021","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1161\/ATVBAHA.109.194803","article-title":"The phosphorylation motif at serine 225 governs the localization and function of sphingosine kinase 1 in resistance arteries","volume":"29","author":"Lidington","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2739","DOI":"10.1161\/CIRCULATIONAHA.111.047316","article-title":"Tumor necrosis factor-alpha-mediated downregulation of the cystic fibrosis transmembrane conductance regulator drives pathological sphingosine-1-phosphate signaling in a mouse model of heart failure","volume":"125","author":"Meissner","year":"2012","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35258","DOI":"10.1074\/jbc.M105442200","article-title":"Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: Modulation of cellular activity of sphingosine 1-phosphate","volume":"276","author":"Boujaoude","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Uhl, F., Vanherle, L., and Meissner, A. (2021). Cystic Fibrosis Transmembrane Regulator Correction Attenuates Heart Failure-Induced Lung Inflammation. Authorea.","DOI":"10.22541\/au.163438687.73515528\/v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E1614","DOI":"10.1073\/pnas.1421190112","article-title":"CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction","volume":"112","author":"Tabeling","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"L530","DOI":"10.1152\/ajplung.00039.2013","article-title":"Cigarette smoke and CFTR: Implications in the pathogenesis of COPD","volume":"305","author":"Rab","year":"2013","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1378\/chest.13-0274","article-title":"Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD","volume":"144","author":"Dransfield","year":"2013","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.lfs.2011.08.018","article-title":"Expression profile of the sphingosine kinase signalling system in the lung of patients with chronic obstructive pulmonary disease","volume":"89","author":"Cordts","year":"2011","journal-title":"Life Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1194\/jlr.M800427-JLR200","article-title":"Defective CFTR increases synthesis and mass of sphingolipids that modulate membrane composition and lipid signaling","volume":"50","author":"Hamai","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Malik, F.A., Meissner, A., Semenkov, I., Molinski, S., Pasyk, S., Ahmadi, S., Bui, H.H., Bear, C.E., Lidington, D., and Bolz, S.S. (2015). Sphingosine-1-Phosphate Is a Novel Regulator of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Activity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0130313"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.molmed.2011.10.003","article-title":"CFTR: Folding, misfolding and correcting the DeltaF508 conformational defect","volume":"18","author":"Lukacs","year":"2012","journal-title":"Trends Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/nchembio.1253","article-title":"Mechanism-based corrector combination restores DeltaF508-CFTR folding and function","volume":"9","author":"Okiyoneda","year":"2013","journal-title":"Nat. Chem. Biol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1111\/bph.14381","article-title":"The emerging alliance of sphingosine-1-phosphate signalling and immune cells: From basic mechanisms to implications in hypertension","volume":"176","author":"Zhang","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2773","DOI":"10.1084\/jem.20160287","article-title":"Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress","volume":"213","author":"Kumar","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3389\/fphar.2017.00335","article-title":"Different Regulation of Interleukin-1 Production and Activity in Monocytes and Macrophages: Innate Memory as an Endogenous Mechanism of IL-1 Inhibition","volume":"8","author":"Madej","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00011-018-1145-8","article-title":"A large lung gene expression study identifying IL1B as a novel player in airway inflammation in COPD airway epithelial cells","volume":"67","author":"Yi","year":"2018","journal-title":"Inflamm. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00281-016-0559-z","article-title":"The IL-1 cytokine family and its role in inflammation and fibrosis in the lung","volume":"38","author":"Borthwick","year":"2016","journal-title":"Semin. Immunopathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s11897-014-0231-7","article-title":"Targeting interleukin-1 in heart failure and inflammatory heart disease","volume":"12","author":"Raleigh","year":"2015","journal-title":"Curr. Heart Fail. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Halilbasic, E., Fuerst, E., Heiden, D., Japtok, L., Diesner, S.C., Trauner, M., Kulu, A., Jaksch, P., Hoetzenecker, K., and Kleuser, B. (2020). Plasma Levels of the Bioactive Sphingolipid Metabolite S1P in Adult Cystic Fibrosis Patients: Potential Target for Immunonutrition?. Nutrients, 12.","DOI":"10.3390\/nu12030765"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1093\/cvr\/cvp070","article-title":"Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection","volume":"82","author":"Sattler","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Hui, S., Levy, A.S., Slack, D.L., Burnstein, M.J., Errett, L., Bonneau, D., Latter, D., Rotstein, O.D., Bolz, S.S., and Lidington, D. (2015). Sphingosine-1-Phosphate Signaling Regulates Myogenic Responsiveness in Human Resistance Arteries. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0138142"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Berdyshev, E.V., Serban, K.A., Schweitzer, K.S., Bronova, I.A., Mikosz, A., and Petrache, I. (2021). Ceramide and sphingosine-1 phosphate in COPD lungs. Thorax.","DOI":"10.1136\/thoraxjnl-2020-215892"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1080\/17476348.2018.1475235","article-title":"CFTR dysfunction in cystic fibrosis and chronic obstructive pulmonary disease","volume":"12","author":"Greene","year":"2018","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/1465-9921-15-69","article-title":"Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels","volume":"15","author":"Hassan","year":"2014","journal-title":"Respir. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1016\/j.bbagen.2015.02.004","article-title":"Cigarette smoke exposure reveals a novel role for the MEK\/ERK1\/2 MAPK pathway in regulation of CFTR","volume":"1850","author":"Xu","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"L1000","DOI":"10.1152\/ajplung.00298.2016","article-title":"Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931","volume":"311","author":"Veltman","year":"2016","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Zulueta, A., Dei Cas, M., Luciano, F., Mingione, A., Pivari, F., Righi, I., Morlacchi, L., Rosso, L., Signorelli, P., and Ghidoni, R. (2021). Spns2 Transporter Contributes to the Accumulation of S1P in Cystic Fibrosis Human Bronchial Epithelial Cells. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091121"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1096\/fj.00-0742fje","article-title":"Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma","volume":"15","author":"Ammit","year":"2001","journal-title":"FASEB J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1164\/rccm.201401-0121OC","article-title":"The sphingosine kinase 1\/sphingosine-1-phosphate pathway in pulmonary arterial hypertension","volume":"190","author":"Chen","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.jbior.2014.09.008","article-title":"Sphingolipids in pulmonary fibrosis","volume":"57","author":"Huang","year":"2015","journal-title":"Adv. Biol. Regul."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1194\/jlr.M026039","article-title":"Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression","volume":"53","author":"Gorshkova","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.jcf.2015.10.011","article-title":"Non-allergic asthma as a CFTR-related disorder","volume":"15","author":"Schulz","year":"2016","journal-title":"J. Cyst. Fibros."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1007\/s004390100467","article-title":"CFTR gene mutations\u2014Including three novel nucleotide substitutions\u2014And haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease","volume":"108","author":"Tzetis","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1189\/jlb.0412188","article-title":"Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection","volume":"92","author":"Bonfield","year":"2012","journal-title":"J. Leukoc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"C1398","DOI":"10.1152\/ajpcell.1994.267.5.C1398","article-title":"Interferon-gamma downregulates CFTR gene expression in epithelial cells","volume":"267","author":"Besancon","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1165\/rcmb.2012-0430OC","article-title":"Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs","volume":"49","author":"Ramachandran","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1164\/rccm.201304-0733OC","article-title":"Cigarette smoke induces systemic defects in cystic fibrosis transmembrane conductance regulator function","volume":"188","author":"Raju","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"13655","DOI":"10.1038\/s41598-019-49544-9","article-title":"Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum","volume":"9","author":"Marklew","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.imbio.2017.11.001","article-title":"Macrophages: Their role, activation and polarization in pulmonary diseases","volume":"223","author":"Arora","year":"2018","journal-title":"Immunobiology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"454","DOI":"10.3389\/fimmu.2018.00454","article-title":"CD86 Expression by Monocytes Influences an Immunomodulatory Profile in Asymptomatic Patients with Chronic Chagas Disease","volume":"9","author":"Pinto","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1165\/rcmb.2012-0021OC","article-title":"Low sphingosine-1-phosphate impairs lung dendritic cells in cystic fibrosis","volume":"48","author":"Xu","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1159\/000362992","article-title":"Sphingosine 1-phosphate in blood: Function, metabolism, and fate","volume":"34","author":"Thuy","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4969","DOI":"10.1038\/s41598-018-23300-x","article-title":"MFSD2B is a sphingosine 1-phosphate transporter in erythroid cells","volume":"8","author":"Kobayashi","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nature24053","article-title":"Mfsd2b is essential for the sphingosine-1-phosphate export in erythrocytes and platelets","volume":"550","author":"Vu","year":"2017","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1080\/09687860600738304","article-title":"Reduced number of CFTR molecules in erythrocyte plasma membrane of cystic fibrosis patients","volume":"23","author":"Lange","year":"2006","journal-title":"Mol. Membr. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1172\/JCI129635","article-title":"Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation","volume":"130","author":"Yu","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Hisano, Y., Kobayashi, N., Yamaguchi, A., and Nishi, T. (2012). Mouse SPNS2 functions as a sphingosine-1-phosphate transporter in vascular endothelial cells. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0038941"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6667","DOI":"10.1074\/jbc.M102841200","article-title":"Extracellular export of sphingosine kinase-1 enzyme. Sphingosine 1-phosphate generation and the induction of angiogenic vascular maturation","volume":"277","author":"Ancellin","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Berdyshev, E.V., Gorshkova, I., Usatyuk, P., Kalari, S., Zhao, Y., Pyne, N.J., Pyne, S., Sabbadini, R.A., Garcia, J.G., and Natarajan, V. (2011). Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: Role of sphingosine kinase 1 and S1P lyase. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0016571"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1161\/CIRCRESAHA.107.165845","article-title":"Vascular endothelium as a contributor of plasma sphingosine 1-phosphate","volume":"102","author":"Venkataraman","year":"2008","journal-title":"Circ. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1172\/JCI116966","article-title":"Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization","volume":"93","author":"Strong","year":"1994","journal-title":"J. Clin. Investig."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e016799","DOI":"10.1161\/JAHA.120.016799","article-title":"Heterozygous Cystic Fibrosis Transmembrane Regulator Gene Missense Variants Are Associated with Worse Cardiac Function in Patients with Duchenne Muscular Dystrophy","volume":"9","author":"Jiang","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1016\/S2213-2600(16)30047-9","article-title":"Pilot evaluation of ivacaftor for chronic bronchitis","volume":"4","author":"Solomon","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"19814","DOI":"10.1038\/srep19814","article-title":"Regulation of human cerebro-microvascular endothelial baso-lateral adhesion and barrier function by S1P through dual involvement of S1P1 and S1P2 receptors","volume":"6","author":"Wiltshire","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1086\/675989","article-title":"Loss of cystic fibrosis transmembrane conductance regulator impairs lung endothelial cell barrier function and increases susceptibility to microvascular damage from cigarette smoke","volume":"4","author":"Brown","year":"2014","journal-title":"Pulm. Circ."},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Heiberg, E., Sjogren, J., Ugander, M., Carlsson, M., Engblom, H., and Arheden, H. (2010). Design and validation of Segment-freely available software for cardiovascular image analysis. BMC Med. Imaging, 10.","DOI":"10.1186\/1471-2342-10-1"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-61779-800-9_3","article-title":"Quantification of sphingosine-1-phosphate and related sphingolipids by liquid chromatography coupled to tandem mass spectrometry","volume":"874","author":"Bode","year":"2012","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/866\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:17Z","timestamp":1760362037000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/866"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,14]]},"references-count":81,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020866"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020866","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,14]]}}}