{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T12:10:16Z","timestamp":1778760616433,"version":"3.51.4"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Sphingolipids are bioactive lipids involved in the regulation of cell survival, proliferation, and the inflammatory response. The SphK\/S1P\/S1PR pathway (S1P pathway) is a driver of many anti-apoptotic and proliferative processes. Pro-survival sphingolipid sphingosine-1-phosphate (S1P) initiates its signaling cascade by interacting with various sphingosine-1-phosphate receptors (S1PR) through which it is able to exert its pro-survival or inflammatory effects. Whereas sphingolipids, including ceramides and sphingosines are pro-apoptotic. The pro-apoptotic lipid, ceramide, can be produced <jats:italic>de novo<\/jats:italic> by ceramide synthases and converted to sphingosine by way of ceramidases. The balance of these antagonistic lipids and how this balance manifests is the essence of the sphingolipid rheostat. Recent studies on SARS-CoV-2 have implicated the S1P pathway in the pathogenesis of novel coronavirus disease COVID-19-related lung damage. Accumulating evidence indicates that an aberrant inflammatory process, known as \u201ccytokine storm\u201d causes lung injury in COVID-19, and studies have shown that the S1P pathway is involved in signaling this hyperinflammatory response. Beyond the influence of this pathway on cytokine storm, over the last decade the S1P pathway has been investigated for its role in a wide array of lung pathologies, including pulmonary fibrosis, pulmonary arterial hypertension (PAH), and lung cancer. Various studies have used S1P pathway modulators in models of lung disease; many of these efforts have yielded results that point to the potential efficacy of targeting this pathway for future treatment options. Additionally, they have emphasized S1P pathway\u2019s significant role in inflammation, fibrosis, and a number of other endothelial and epithelial changes that contribute to lung damage. This review summarizes the S1P pathway\u2019s involvement in COVID-19 and chronic lung diseases and discusses the potential for targeting S1P pathway as a therapeutic option for these diseases.<\/jats:p>","DOI":"10.3389\/fphys.2021.760638","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T17:34:11Z","timestamp":1633887251000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":28,"title":["Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage"],"prefix":"10.3389","volume":"12","author":[{"given":"Saad A.","family":"Khan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla F.","family":"Goliwas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessy S.","family":"Deshane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"6354","DOI":"10.1111\/febs.12446","article-title":"Sphingosine-1-phosphate receptor 2.","volume":"280","author":"Adada","year":"2013","journal-title":"FEBS J."},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-020-01278-8","article-title":"Alveolar lipids in pulmonary disease. A review.","volume":"19","author":"Agudelo","year":"2020","journal-title":"Lipids Health Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1038\/nature09128","article-title":"Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2.","volume":"465","author":"Alvarez","year":"2010","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3472","DOI":"10.1016\/j.celrep.2019.11.036","article-title":"Sphingosine-1-Phosphate Receptor 1 Activity Promotes Tumor Growth by Amplifying VEGF-VEGFR2 Angiogenic Signaling.","volume":"29","author":"Balaji Ragunathrao","year":"2019","journal-title":"Cell Rep."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000753","article-title":"COVID-19 infection in a patient with multiple sclerosis treated with fingolimod.","volume":"7","author":"Barzegar","year":"2020","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2020.106239","article-title":"Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians.","volume":"176","author":"Batah","year":"2021","journal-title":"Respir. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/sj.onc.1208019","article-title":"Sphingosine kinase activity counteracts ceramide-mediated cell death in human melanoma cells: role of Bcl-2 expression.","volume":"24","author":"Bektas","year":"2005","journal-title":"Oncogene"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cells9102201","article-title":"Dissecting Gq\/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1.","volume":"9","author":"Blankenbach","year":"2020","journal-title":"Cells"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.646688","article-title":"Immune Profile in Patients With COVID-19: Lymphocytes Exhaustion Markers in Relationship to Clinical Outcome.","volume":"11","author":"Bobcakova","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2021.05.022","article-title":"Novel SARS-CoV-2 variants: the pandemics within the pandemic.","volume":"2021","author":"Boehm","year":"2021","journal-title":"Clin. Microbiol. Infect."},{"key":"B11","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/978-3-030-68748-9_6","article-title":"Molecular Mechanisms of Vascular Damage During Lung Injury.","volume":"1304","author":"Bossardi Ramos","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1177\/2045894020905521","article-title":"Sphingosine-1-phosphate receptor-independent lung endothelial cell barrier disruption induced by FTY720 regioisomers.","volume":"10","author":"Camp","year":"2020","journal-title":"Pulm. Circ."},{"key":"B13","author":"Cascella","year":"2021","journal-title":"Features, Evaluation, and Treatment of Coronavirus (COVID-19)."},{"key":"B14","year":"2021","journal-title":"SARS-CoV-2 Variant Classifications and Definitions."},{"key":"B15","doi-asserted-by":"publisher","first-page":"44848","DOI":"10.1074\/jbc.M106291200","article-title":"FAS activation induces dephosphorylation of SR proteins; dependence on the de novo generation of ceramide and activation of protein phosphatase 1.","volume":"276","author":"Chalfant","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.bbalip.2012.07.005","article-title":"Post-translational regulation of sphingosine kinases.","volume":"1831","author":"Chan","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.2147\/COPD.S196210","article-title":"Lipid metabolism in chronic obstructive pulmonary disease.","volume":"14","author":"Chen","year":"2019","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"B18","doi-asserted-by":"publisher","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":"B19","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.phrs.2016.09.025","article-title":"To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.","author":"Chew","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1111\/joim.12019","article-title":"VEGFA and tumour angiogenesis.","volume":"273","author":"Claesson-Welsh","year":"2013","journal-title":"J. Intern. Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1177\/2040622315617354","article-title":"Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases.","volume":"7","author":"D\u2019Ambrosio","year":"2016","journal-title":"Ther. Adv. Chronic. Dis."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1833","DOI":"10.1016\/j.jiph.2020.07.014","article-title":"COVID-19 and comorbidities: Deleterious impact on infected patients.","volume":"13","author":"Ejaz","year":"2020","journal-title":"J. Infect. Public Health"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2020.04.014","article-title":"Severe COVID-19 infection associated with endothelial activation.","volume":"190","author":"Escher","year":"2020","journal-title":"Thromb. Res."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.10592","article-title":"TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1.","volume":"4","author":"Etemadi","year":"2015","journal-title":"Elife"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2020.104999","article-title":"Ponesimod suppresses hepatitis B virus infection by inhibiting endosome maturation.","volume":"186","author":"Fauzyah","year":"2021","journal-title":"Antiviral Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.2147\/DDDT.S240861","article-title":"An Overview of the Efficacy and Safety of Ozanimod for the Treatment of Relapsing Multiple Sclerosis.","volume":"15","author":"Fronza","year":"2021","journal-title":"Drug Des. Devel. Ther."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1259","DOI":"10.3892\/ol.2019.10447","article-title":"Sphingosine kinase-1 predicts overall survival outcomes in non-small cell lung cancer patients treated with carboplatin and navelbine.","volume":"18","author":"Gachechiladze","year":"2019","journal-title":"Oncol. Lett."},{"key":"B28","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.pupt.2017.03.010","article-title":"FTY720 promotes pulmonary fibrosis when administered during the remodelling phase following a bleomycin-induced lung injury.","volume":"44","author":"Gendron","year":"2017","journal-title":"Pulm. Pharmacol. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/s41586-020-03148-w","article-title":"Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia.","volume":"590","author":"Grant","year":"2021","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.1176709","article-title":"Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate.","volume":"325","author":"Hait","year":"2009","journal-title":"Science"},{"key":"B31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/nrm2329","article-title":"Principles of bioactive lipid signalling: lessons from sphingolipids.","volume":"9","author":"Hannun","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2019-000354","article-title":"First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.","volume":"6","author":"Hermann","year":"2019","journal-title":"Lupus Sci. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.cell.2020.02.052","article-title":"SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor.","volume":"181","author":"Hoffmann","year":"2020","journal-title":"Cell"},{"key":"B34","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1002\/jmv.26232","article-title":"The cytokine storm and COVID-19.","volume":"93","author":"Hu","year":"2021","journal-title":"J. Med. Virol."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21062064","article-title":"Sphingosine Kinase 1\/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo\/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts.","volume":"21","author":"Huang","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.01169","article-title":"Cellular and Molecular Pathways of COVID-19 and Potential Points of Therapeutic Intervention.","volume":"11","author":"Hussman","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1007\/s12035-018-1040-x","article-title":"Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer\u2019s Disease.","volume":"56","author":"Jesko","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12977","article-title":"COVID-19 and pulmonary fibrosis: A potential role for lung epithelial cells and fibroblasts.","author":"John","year":"2021","journal-title":"Immunol. Rev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1159","DOI":"10.1369\/jhc.4A6606.2005","article-title":"Immunohistochemical distribution of sphingosine kinase 1 in normal and tumor lung tissue.","volume":"53","author":"Johnson","year":"2005","journal-title":"J. Histochem. Cytochem."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.589380","article-title":"T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis.","volume":"11","author":"Kalfaoglu","year":"2020","journal-title":"Front. Immunol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.bbrc.2020.10.079","article-title":"T-cell dysregulation in COVID-19.","volume":"538","author":"Kalfaoglu","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.ijid.2020.05.106","article-title":"Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity.","volume":"97","author":"Kang","year":"2020","journal-title":"Int. J. Infect. Dis."},{"key":"B43","doi-asserted-by":"publisher","first-page":"281","DOI":"10.2353\/ajpath.2007.060485","article-title":"Immunomodulator FTY720 induces myofibroblast differentiation via the lysophospholipid receptor S1P3 and Smad3 signaling.","volume":"170","author":"Keller","year":"2007","journal-title":"Am. J. Pathol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"36793","DOI":"10.1074\/jbc.M608137200","article-title":"Protein kinase C-induced activation of a ceramide\/protein phosphatase 1 pathway leading to dephosphorylation of p38 MAPK.","volume":"281","author":"Kitatani","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.12703\/P7-26","article-title":"Angiogenesis versus arteriogenesis: neuropilin 1 modulation of VEGF signaling.","volume":"7","author":"Kofler","year":"2015","journal-title":"F1000Prime Rep."},{"key":"B46","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.apsb.2014.12.009","article-title":"Bile acids and sphingosine-1-phosphate receptor 2 in hepatic lipid metabolism.","volume":"5","author":"Kwong","year":"2015","journal-title":"Acta Pharm. Sin B"},{"key":"B47","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.devcel.2010.02.016","article-title":"VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis.","volume":"18","author":"Lanahan","year":"2010","journal-title":"Dev. Cell"},{"key":"B48","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.devcel.2013.03.019","article-title":"The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis.","volume":"25","author":"Lanahan","year":"2013","journal-title":"Dev. Cell"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmii.2021.04.006","article-title":"Immunological map in COVID-19.","author":"Li","year":"2021","journal-title":"J. Microbiol. Immunol. Infect."},{"key":"B50","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1113\/expphysiol.2014.082149","article-title":"Differential activation of receptors and signal pathways upon stimulation by different doses of sphingosine-1-phosphate in endothelial cells.","volume":"100","author":"Li","year":"2015","journal-title":"Exp. Physiol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.cca.2021.03.025","article-title":"Sphingosine-1-phosphate receptor 3 signaling.","volume":"519","author":"Li","year":"2021","journal-title":"Clin. Chim. Acta"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01776","article-title":"S100A4(+) Macrophages Are Necessary for Pulmonary Fibrosis by Activating Lung Fibroblasts.","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"19513","DOI":"10.1074\/jbc.M002759200","article-title":"Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform.","volume":"275","author":"Liu","year":"2000","journal-title":"J. Biol. Chem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"2276","DOI":"10.1158\/0008-5472.CAN-10-3107","article-title":"Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells.","volume":"71","author":"Liu","year":"2011","journal-title":"Cancer Res."},{"key":"B55","doi-asserted-by":"publisher","first-page":"e6","DOI":"10.1016\/j.jinf.2020.04.002","article-title":"Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19.","volume":"81","author":"Liu","year":"","journal-title":"J. Infect."},{"key":"B56","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s11427-020-1643-8","article-title":"Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury.","volume":"63","author":"Liu","year":"","journal-title":"Sci. China Life Sci."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2108891","article-title":"Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant.","author":"Lopez Bernal","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-020-03007-0","article-title":"Neutrophil-to-lymphocyte ratio as a predictive biomarker for moderate-severe ARDS in severe COVID-19 patients.","volume":"24","author":"Ma","year":"2020","journal-title":"Crit. Care"},{"key":"B59","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.cellsig.2016.03.014","article-title":"Effect of the sphingosine kinase 1 selective inhibitor, PF-543 on arterial and cardiac remodelling in a hypoxic model of pulmonary arterial hypertension.","volume":"28","author":"MacRitchie","year":"2016","journal-title":"Cell Signal"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.trsl.2020.04.007","article-title":"Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases.","volume":"220","author":"Magro","year":"2020","journal-title":"Transl. Res."},{"key":"B61","doi-asserted-by":"publisher","first-page":"29078","DOI":"10.1074\/jbc.M110.105296","article-title":"Alkaline ceramidase 2 (ACER2) and its product dihydrosphingosine mediate the cytotoxicity of N-(4-hydroxyphenyl)retinamide in tumor cells.","volume":"285","author":"Mao","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197189","article-title":"Targeting the SphK-S1P-SIPR Pathway as a Potential Therapeutic Approach for COVID-19.","volume":"21","author":"McGowan","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B63","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.jneuroim.2012.03.007","article-title":"Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.","volume":"246","author":"Moberly","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1096\/fj.08-120550","article-title":"Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling.","volume":"23","author":"Mukhopadhyay","year":"2009","journal-title":"FASEB J."},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106792","article-title":"Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.","volume":"9","author":"Murakami","year":"2014","journal-title":"PLoS One"},{"key":"B66","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1165\/rcmb.2012-0411TR","article-title":"Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury.","volume":"49","author":"Natarajan","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B67","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/nrc.2017.96","article-title":"Sphingolipid metabolism in cancer signalling and therapy.","volume":"18","author":"Ogretmen","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaa4998","article-title":"Binding of the sphingolipid S1P to hTERT stabilizes telomerase at the nuclear periphery by allosterically mimicking protein phosphorylation.","volume":"8","author":"Panneer Selvam","year":"2015","journal-title":"Sci. Signal"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1186\/s13027-021-00369-0","article-title":"Lung histopathological findings in COVID-19 disease - a systematic review.","volume":"16","author":"Pannone","year":"2021","journal-title":"Infect. Agent Cancer"},{"key":"B70","doi-asserted-by":"publisher","first-page":"3638","DOI":"10.1096\/fj.14-261289","article-title":"Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-gamma that regulates neoangiogenesis.","volume":"29","author":"Parham","year":"2015","journal-title":"FASEB J."},{"key":"B71","doi-asserted-by":"publisher","first-page":"318","DOI":"10.4062\/biomolther.2018.131","article-title":"Deficiency of Sphingosine-1-Phosphate Receptor 2 (S1P2) Attenuates Bleomycin-Induced Pulmonary Fibrosis.","volume":"27","author":"Park","year":"2019","journal-title":"Biomol. Ther."},{"key":"B72","doi-asserted-by":"publisher","first-page":"11667","DOI":"10.1158\/0008-5472.CAN-05-2702","article-title":"Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models.","volume":"65","author":"Pchejetski","year":"2005","journal-title":"Cancer Res."},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-021-01528-8","article-title":"Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis.","author":"Perez-Jeldres","year":"2021","journal-title":"Drugs"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aax8050","article-title":"A G protein-biased S1P1 agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers.","volume":"13","author":"Poirier","year":"2020","journal-title":"Sci. Signal"},{"key":"B75","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.2217\/fon.10.116","article-title":"Sphingolipids and cancer: ceramide and sphingosine-1-phosphate in the regulation of cell death and drug resistance.","volume":"6","author":"Ponnusamy","year":"2010","journal-title":"Fut. Oncol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1002\/emmm.201200244","article-title":"Communication between host organism and cancer cells is transduced by systemic sphingosine kinase 1\/sphingosine 1-phosphate signalling to regulate tumour metastasis.","volume":"4","author":"Ponnusamy","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3390\/ph13100298","article-title":"Impact of S1P Mimetics on Mesenteric Ischemia\/Reperfusion Injury.","volume":"13","author":"Poti","year":"2020","journal-title":"Pharmaceuticals"},{"key":"B78","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1159\/000315107","article-title":"Phosphorylation of the immunomodulator FTY720 inhibits programmed cell death of fibroblasts via the S1P3 receptor subtype and Bcl-2 activation.","volume":"26","author":"Potteck","year":"2010","journal-title":"Cell Physiol. Biochem."},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2020.106504","article-title":"Host sphingolipids: Perspective immune adjuvant for controlling SARS-CoV-2 infection for managing COVID-19 disease.","volume":"152","author":"Prakash","year":"2021","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2020.158630","article-title":"Novel signaling aspects of ceramide 1-phosphate.","volume":"1865","author":"Presa","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"B81","doi-asserted-by":"publisher","first-page":"2131","DOI":"10.1089\/neu.2019.6951","article-title":"Fingolimod Attenuates Lung Injury and Cardiac Dysfunction after Traumatic Brain Injury.","volume":"37","author":"Qian","year":"2020","journal-title":"J. Neurotrauma"},{"key":"B82","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1172\/JCI39837","article-title":"ERK1\/2-Akt1 crosstalk regulates arteriogenesis in mice and zebrafish.","volume":"120","author":"Ren","year":"2010","journal-title":"J. Clin. Invest."},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102433","article-title":"The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak.","volume":"109","author":"Rothan","year":"2020","journal-title":"J. Autoimmun."},{"key":"B84","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/B978-0-12-394274-6.00002-9","article-title":"Diverse functions of ceramide in cancer cell death and proliferation.","volume":"117","author":"Saddoughi","year":"2013","journal-title":"Adv. Cancer Res."},{"key":"B85","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1002\/emmm.201201283","article-title":"Sphingosine analogue drug FTY720 targets I2PP2A\/SET and mediates lung tumour suppression via activation of PP2A-RIPK1-dependent necroptosis.","volume":"5","author":"Saddoughi","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1056\/NEJMoa1513248","article-title":"Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis.","volume":"374","author":"Sandborn","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B87","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1165\/rcmb.2009-0345OC","article-title":"Prolonged exposure to sphingosine 1-phosphate receptor-1 agonists exacerbates vascular leak, fibrosis, and mortality after lung injury.","volume":"43","author":"Shea","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"365","DOI":"10.3109\/10409238.2011.580097","article-title":"The compartmentalization and translocation of the sphingosine kinases: mechanisms and functions in cell signaling and sphingolipid metabolism.","volume":"46","author":"Siow","year":"2011","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"14839","DOI":"10.1074\/jbc.M112.426726","article-title":"Sphingosine 1-phosphate (S1P) receptor agonists mediate pro-fibrotic responses in normal human lung fibroblasts via S1P2 and S1P3 receptors and Smad-independent signaling.","volume":"288","author":"Sobel","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B90","doi-asserted-by":"publisher","first-page":"8253","DOI":"10.18632\/oncotarget.6982","article-title":"Targeting glucosylceramide synthase upregulation reverts sorafenib resistance in experimental hepatocellular carcinoma.","volume":"7","author":"Stefanovic","year":"2016","journal-title":"Oncotarget"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.02.009","article-title":"Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseases.","volume":"154","author":"Stepanovska","year":"2020","journal-title":"Pharmacol. Res."},{"key":"B92","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1096\/fj.10-167502","article-title":"Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration.","volume":"25","author":"Strub","year":"2011","journal-title":"FASEB J."},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21124257","article-title":"Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways.","volume":"21","author":"Suryadevara","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"B94","doi-asserted-by":"publisher","first-page":"1902","DOI":"10.1177\/0961203320966385","article-title":"Amiselimod, a sphingosine 1-phosphate receptor-1 modulator, for systemic lupus erythematosus: A multicenter, open-label exploratory study.","volume":"29","author":"Tanaka","year":"2020","journal-title":"Lupus"},{"key":"B95","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1073\/pnas.1400593111","article-title":"Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection.","volume":"111","author":"Teijaro","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B96","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.bbalip.2009.01.019","article-title":"Galpha(q)-mediated plasma membrane translocation of sphingosine kinase-1 and cross-activation of S1P receptors.","volume":"1791","author":"ter Braak","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"B97","year":"2019","journal-title":"FDA approves new oral drug to treat multiple sclerosis."},{"key":"B98","year":"2020","journal-title":"Novel Drug Approvals for 2020."},{"key":"B99","year":"2021","journal-title":"Novel Drug Approvals for 2021."},{"key":"B100","year":"2020","journal-title":"COVID-19 Ozanimod Intervention Study (COZI)."},{"key":"B101","doi-asserted-by":"publisher","first-page":"2036","DOI":"10.1016\/S0140-6736(14)60803-5","article-title":"Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial.","volume":"384","author":"Vaclavkova","year":"2014","journal-title":"Lancet"},{"key":"B102","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nature20792","article-title":"Genome-wide in vivo screen identifies novel host regulators of metastatic colonization.","volume":"541","author":"van der Weyden","year":"2017","journal-title":"Nature"},{"key":"B103","doi-asserted-by":"publisher","first-page":"6281","DOI":"10.1128\/JVI.00464-14","article-title":"Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy.","volume":"88","author":"Walsh","year":"2014","journal-title":"J. Virol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1194\/jlr.R600003-JLR200","article-title":"The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function.","volume":"47","author":"Wattenberg","year":"2006","journal-title":"J. Lipid Res."},{"key":"B105","doi-asserted-by":"publisher","first-page":"2695","DOI":"10.1084\/jem.20160392","article-title":"S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3\/IL-1beta.","volume":"214","author":"Weichand","year":"2017","journal-title":"J. Exp. Med."},{"key":"B106","year":"2021","journal-title":"RAPID ACT-ACCELERATOR DELTA RESPONSE (RADAR)."},{"key":"B107","year":"2020","journal-title":"SARS-CoV-2 Variants. Disease Outbreak News."},{"key":"B108","year":"2021","journal-title":"COVID-19 Weekly Epidemiological Update."},{"key":"B109","doi-asserted-by":"publisher","first-page":"32563","DOI":"10.1074\/jbc.M113.483750","article-title":"Sphingosine kinases are not required for inflammatory responses in macrophages.","volume":"288","author":"Xiong","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B110","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1002\/cpdd.98","article-title":"Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers.","volume":"3","author":"Xu","year":"2014","journal-title":"Clin. Pharmacol. Drug Dev."},{"key":"B111","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1096\/fj.05-5689com","article-title":"Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P.","volume":"20","author":"Xu","year":"2006","journal-title":"FASEB J."},{"key":"B112","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/j.bbrc.2019.06.160","article-title":"S1P induces pulmonary artery smooth muscle cell proliferation by activating calcineurin\/NFAT\/OPN signaling pathway.","volume":"516","author":"Yan","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B113","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1182\/blood-2007-11-125203","article-title":"Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1\/Gi\/PLC\/Ca2+ signaling pathways.","volume":"112","author":"Yoon","year":"2008","journal-title":"Blood"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2020.114296","article-title":"Repurposing existing drugs for the treatment of COVID-19\/SARS-CoV-2 infection: A review describing drug mechanisms of action.","volume":"183","author":"Yousefi","year":"2021","journal-title":"Biochem. Pharmacol."},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197604","article-title":"Sphingosine-1-phosphate receptor-2 facilitates pulmonary fibrosis through potentiating IL-13 pathway in macrophages.","volume":"13","author":"Zhao","year":"2018","journal-title":"PLoS One"},{"key":"B116","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1096\/fj.201600751R","article-title":"Neuroprotective effects of fingolimod in mouse models of Parkinson\u2019s disease.","volume":"31","author":"Zhao","year":"2017","journal-title":"FASEB J."},{"key":"B117","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1093\/nsr\/nwaa041","article-title":"Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients.","volume":"7","author":"Zhou","year":"2020","journal-title":"Natl. Sci. Rev."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.760638\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T17:34:15Z","timestamp":1633887255000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2021.760638\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,8]]},"references-count":117,"alternative-id":["10.3389\/fphys.2021.760638"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2021.760638","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,8]]},"article-number":"760638"}}