{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T23:00:52Z","timestamp":1762642852731,"version":"build-2065373602"},"reference-count":115,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T00:00:00Z","timestamp":1679529600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170093"],"award-info":[{"award-number":["82170093"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Dyspnea and progressive hypoxemia are the main clinical features of patients with coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary pathology shows diffuse alveolar damage with edema, hemorrhage, and the deposition of fibrinogens in the alveolar space, which are consistent with the Berlin Acute Respiratory Distress Syndrome Criteria. The epithelial sodium channel (ENaC) is a key channel protein in alveolar ion transport and the rate-limiting step for pulmonary edema fluid clearance, the dysregulation of which is associated with acute lung injury\/acute respiratory distress syndrome. The main protein of the fibrinolysis system, plasmin, can bind to the furin site of \u03b3-ENaC and induce it to an activation state, facilitating pulmonary fluid reabsorption. Intriguingly, the unique feature of SARS-CoV-2 from other \u03b2-coronaviruses is that the spike protein of the former has the same furin site (RRAR) with ENaC, suggesting that a potential competition exists between SARS-CoV-2 and ENaC for the cleavage by plasmin. Extensive pulmonary microthrombosis caused by disorders of the coagulation and fibrinolysis system has also been seen in COVID-19 patients. To some extent, high plasmin (ogen) is a common risk factor for SARS-CoV-2 infection since an increased cleavage by plasmin accelerates virus invasion. This review elaborates on the closely related relationship between SARS-CoV-2 and ENaC for fibrinolysis system-related proteins, aiming to clarify the regulation of ENaC under SARS-CoV-2 infection and provide a novel reference for the treatment of COVID-19 from the view of sodium transport regulation in the lung epithelium.<\/jats:p>","DOI":"10.3390\/biom13040578","type":"journal-article","created":{"date-parts":[[2023,3,23]],"date-time":"2023-03-23T03:07:57Z","timestamp":1679540877000},"page":"578","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Regulation of Epithelial Sodium Transport by SARS-CoV-2 Is Closely Related with Fibrinolytic System-Associated Proteins"],"prefix":"10.3390","volume":"13","author":[{"given":"Tingyu","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3505-2700","authenticated-orcid":false,"given":"Yiman","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9973-6354","authenticated-orcid":false,"given":"Hongguang","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang 110122, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2249","DOI":"10.1002\/jmv.26234","article-title":"Emerging coronaviruses: Genome structure, replication, and pathogenesis","volume":"92","author":"Chen","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1080\/22221751.2020.1719902","article-title":"Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan","volume":"9","author":"Chan","year":"2020","journal-title":"Emerg. Microbes Infect."},{"key":"ref_3","doi-asserted-by":"crossref","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":"ref_4","first-page":"226","article-title":"Molecular aspects of co-morbidities in COVID-19 infection","volume":"8","author":"Pouya","year":"2020","journal-title":"Arch. Bone Jt. Surg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"104742","DOI":"10.1016\/j.antiviral.2020.104742","article-title":"The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade","volume":"176","author":"Coutard","year":"2020","journal-title":"Antivir. Res"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cell.2020.02.058","article-title":"Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein","volume":"181","author":"Walls","year":"2020","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.cell.2020.11.020","article-title":"Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity","volume":"184","author":"Volz","year":"2021","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"110829","DOI":"10.1016\/j.celrep.2022.110829","article-title":"Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant","volume":"39","author":"Liu","year":"2022","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1016\/j.cell.2020.09.032","article-title":"Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant","volume":"183","author":"Yurkovetskiy","year":"2020","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1152\/physrev.00019.2020","article-title":"Anti-protease treatments targeting plasmin(ogen) and neutrophil elastase may be beneficial in fighting COVID-19","volume":"100","author":"Thierry","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41577-022-00762-9","article-title":"Understanding COVID-19-associated coagulopathy","volume":"22","author":"Conway","year":"2022","journal-title":"Nat. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1152\/physrev.00013.2020","article-title":"Elevated plasmin(ogen) as a common risk factor for COVID-19 susceptibility","volume":"100","author":"Ji","year":"2020","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e58603","DOI":"10.7554\/eLife.58603","article-title":"SARS-CoV-2 strategically mimics proteolytic activation of human ENaC","volume":"9","author":"Anand","year":"2020","journal-title":"eLife"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Brown, E.F., Mitaera, T., and Fronius, M. (2022). COVID-19 and liquid homeostasis in the lung-a perspective through the epithelial sodium channel (ENaC) lens. Cells, 11.","DOI":"10.3390\/cells11111801"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Papa, G., Mallery, D.L., Albecka, A., Welch, L.G., Cattin-Ortol\u00e1, J., Luptak, J., Paul, D., McMahon, H.T., Goodfellow, I.G., and Carter, A. (2021). Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009246"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"F1","DOI":"10.1152\/ajprenal.00277.2019","article-title":"Membrane trafficking pathways regulating the epithelial Na+ channel","volume":"318","author":"Ware","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2805","DOI":"10.1016\/j.bpj.2021.06.005","article-title":"Regulation of epithelial sodium channel activity by SARS-CoV-1 and SARS-CoV-2 proteins","volume":"120","author":"Grant","year":"2021","journal-title":"Biophys. J."},{"key":"ref_18","first-page":"252","article-title":"Acute lung injury and the acute respiratory distress syndrome: Pathophysiology and treatment","volume":"107","author":"Matuschak","year":"2010","journal-title":"Mo. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"345","DOI":"10.5858\/arpa.2015-0519-RA","article-title":"Acute lung injury: A clinical and molecular review","volume":"140","author":"Butt","year":"2016","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_20","first-page":"1009","article-title":"The acute respiratory distress syndrome: Mechanisms and perspective therapeutic approaches","volume":"2","author":"Gonzales","year":"2015","journal-title":"Austin J. Vasc. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/S0140-6736(21)00439-6","article-title":"Acute respiratory distress syndrome","volume":"398","author":"Meyer","year":"2021","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"664349","DOI":"10.3389\/fphar.2021.664349","article-title":"Pulmonary edema in COVID-19 patients: Mechanisms and treatment potential","volume":"12","author":"Cui","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F377","DOI":"10.1152\/ajprenal.00143.2002","article-title":"Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport","volume":"283","author":"Kamynina","year":"2002","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F684","DOI":"10.1152\/ajprenal.00259.2011","article-title":"ENaC structure and function in the wake of a resolved structure of a family member","volume":"301","author":"Kashlan","year":"2011","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1152\/physrev.00007.2002","article-title":"Epithelial sodium channel\/degenerin family of ion channels: A variety of functions for a shared structure","volume":"82","author":"Kellenberger","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1113\/EP087590","article-title":"Peripheral localization of the epithelial sodium channel in the apical membrane of bronchial epithelial cells","volume":"104","author":"Musante","year":"2019","journal-title":"Exp. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s12026-021-09176-6","article-title":"Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K\/Akt\/Nedd4-2 pathway in LPS-induced acute lung injury","volume":"69","author":"Jiang","year":"2021","journal-title":"Immunol. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1038\/s41379-021-00814-w","article-title":"Histopathological findings and clinicopathologic correlation in COVID-19: A systematic review","volume":"34","author":"Caramaschi","year":"2021","journal-title":"Mod. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1056\/NEJMc2013020","article-title":"Natural history of asymptomatic SARS-CoV-2 infection","volume":"383","author":"Sakurai","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1056\/NEJMoa2008457","article-title":"Presymptomatic SARS-CoV-2 infections and transmission in a skilled nursing facility","volume":"382","author":"Arons","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_31","first-page":"2526","article-title":"Acute respiratory distress syndrome: The Berlin definition","volume":"307","author":"Ranieri","year":"2012","journal-title":"JAMA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R132","DOI":"10.1186\/cc12811","article-title":"Relationship between extravascular lung water and severity categories of acute respiratory distress syndrome by the Berlin definition","volume":"17","author":"Kushimoto","year":"2013","journal-title":"Crit. Care"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s13054-021-03594-6","article-title":"COVID-19 ARDS is characterized by higher extravascular lung water than non-COVID-19 ARDS: The PiCCOVID study","volume":"25","author":"Shi","year":"2021","journal-title":"Crit. Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11524","DOI":"10.1038\/s41598-021-91043-3","article-title":"Increased extravascular lung water index (EVLWI) reflects rapid non-cardiogenic oedema and mortality in COVID-19 associated ARDS","volume":"11","author":"Rasch","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"F444","DOI":"10.1152\/ajprenal.00604.2018","article-title":"Effects of reactive oxygen species on renal tubular transport","volume":"317","author":"Hong","year":"2019","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"L410","DOI":"10.1152\/ajplung.00260.2011","article-title":"Nadph oxidase regulates alveolar epithelial sodium channel activity and lung fluid balance in vivo via O2\u2212 signaling","volume":"302","author":"Goodson","year":"2012","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"L374","DOI":"10.1152\/ajplung.00040.2014","article-title":"ENaC activity and expression is decreased in the lungs of protein kinase C-\u03b1 knockout mice","volume":"307","author":"Eaton","year":"2014","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"E374","DOI":"10.1073\/pnas.1306798111","article-title":"TGF-\u03b2 directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury","volume":"111","author":"Peters","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1016\/j.devcel.2021.10.006","article-title":"ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress","volume":"56","author":"Chen","year":"2021","journal-title":"Dev. Cell"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Vaz de Paula, C.B., Nagashima, S., Liberalesso, V., Collete, M., da Silva, F.P.G., Oricil, A.G.G., Barbosa, G.S., da Silva, G.V.C., Wiedmer, D.B., and da Silva Dezid\u00e9rio, F. (2021). COVID-19: Immunohistochemical analysis of TGF-\u03b2 signaling pathways in pulmonary fibrosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010168"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Huntington, K.E., Carlsen, L., So, E.Y., Piesche, M., Liang, O., and El-Deiry, W.S. (2022). Integrin\/TGF-\u03b21 inhibitor GLPG-0187 blocks SARS-CoV-2 delta and omicron pseudovirus infection of airway epithelial cells in vitro, which could attenuate disease severity. Pharmaceuticals, 15.","DOI":"10.1101\/2022.01.02.22268641"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14600","DOI":"10.1038\/s41598-021-94118-3","article-title":"Mechanisms and consequences of casein kinase II and ankyrin-3 regulation of the epithelial Na(+) channel","volume":"11","author":"Soares","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.cell.2020.06.034","article-title":"The global phosphorylation landscape of SARS-CoV-2 infection","volume":"182","author":"Bouhaddou","year":"2020","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"F367","DOI":"10.1152\/ajprenal.00469.2017","article-title":"Physiological regulation of the epithelial Na(+) channel by casein kinase II","volume":"314","author":"Berman","year":"2018","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/s41392-021-00567-7","article-title":"Protein kinase CK2: A potential therapeutic target for diverse human diseases","volume":"6","author":"Borgo","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"8338","DOI":"10.1074\/jbc.M105044200","article-title":"Regulation of the epithelial sodium channel by serine proteases in human airways","volume":"277","author":"Donaldson","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7635","DOI":"10.1038\/s41598-020-64368-8","article-title":"Inhibition of Influenza A virus propagation by benzoselenoxanthenes stabilizing TMPRSS2 Gene G-quadruplex and hence down-regulating TMPRSS2 expression","volume":"10","author":"Shen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Muhanna, D., Arnipalli, S.R., Kumar, S.B., and Ziouzenkova, O. (2020). Osmotic Adaptation by Na(+)-Dependent Transporters and ACE2: Correlation with Hemostatic Crisis in COVID-19. Biomedicines, 8.","DOI":"10.3390\/biomedicines8110460"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6655","DOI":"10.1007\/s11033-021-06642-0","article-title":"How SARS-CoV-2 might affect potassium balance via impairing epithelial sodium channels?","volume":"48","author":"Noori","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/ajh\/hpaa223","article-title":"SARS-CoV-2 receptor ACE2 gene is associated with hypertension and severity of COVID 19: Interaction with sex, obesity, and smoking","volume":"34","author":"Hamet","year":"2021","journal-title":"Am. J. Hypertens."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1007\/s00253-021-11319-6","article-title":"Potential role of IFN-\u03b1 in COVID-19 patients and its underlying treatment options","volume":"105","author":"Yang","year":"2021","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"R763","DOI":"10.1152\/ajpregu.00207.2022","article-title":"Epithelial sodium channels in macrophage migration and polarization: Role of proinflammatory cytokines TNF\u03b1 and IFN\u03b3","volume":"323","author":"Nemeth","year":"2022","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1007\/s12079-019-00533-7","article-title":"IL-1 promotes \u03b1-epithelial Sodium Channel (\u03b1-ENaC) expression in murine lung epithelial cells: Involvement of NF-\u03baB","volume":"14","author":"Mustafa","year":"2020","journal-title":"J. Cell Commun. Signal."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1126\/science.abc6027","article-title":"Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients","volume":"369","author":"Hadjadj","year":"2020","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.resp.2008.12.008","article-title":"The regulation of amiloride-sensitive epithelial sodium channels by tumor necrosis factor-alpha in injured lungs and alveolar type II cells","volume":"166","author":"Yamagata","year":"2009","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"142","DOI":"10.2302\/kjm.54.142","article-title":"Coagulation and fibrinolysis in human acute lung injury--new therapeutic targets?","volume":"54","author":"Ware","year":"2005","journal-title":"Keio J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/ajcp\/aqaa062","article-title":"COVID-19 autopsies, Oklahoma, USA","volume":"153","author":"Barton","year":"2020","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/his.14134","article-title":"Postmortem examination of COVID-19 patients reveals diffuse alveolar damage with severe capillary congestion and variegated findings in lungs and other organs suggesting vascular dysfunction","volume":"77","author":"Menter","year":"2020","journal-title":"Histopathology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1177\/1358863X20932640","article-title":"COVID-19-associated coagulopathy: An exploration of mechanisms","volume":"25","author":"Colling","year":"2020","journal-title":"Vasc. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1007\/s00414-020-02317-w","article-title":"Dying with SARS-CoV-2 infection-an autopsy study of the first consecutive 80 cases in Hamburg, Germany","volume":"134","author":"Edler","year":"2020","journal-title":"Int. J. Leg. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"693","DOI":"10.21037\/atm-20-3989","article-title":"COVID-19: Unravelling the clinical progression of nature\u2019s virtually perfect biological weapon","volume":"8","author":"Lippi","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1111\/jth.14830","article-title":"Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia","volume":"18","author":"Cui","year":"2020","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3389\/fmed.2016.00064","article-title":"Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study","volume":"3","author":"Ozolina","year":"2016","journal-title":"Front. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s12931-020-01372-6","article-title":"SN50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome mice through inhibiting NF-\u03baB p65 translocation","volume":"21","author":"Wu","year":"2020","journal-title":"Respir. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.2174\/138920111798281171","article-title":"Therapeutic modulation of coagulation and fibrinolysis in acute lung injury and the acute respiratory distress syndrome","volume":"12","author":"Sebag","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.ajpath.2013.03.022","article-title":"Regulation of lung injury and fibrosis by p53-mediated changes in urokinase and plasminogen activator inhibitor-1","volume":"183","author":"Bhandary","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/s41419-021-04070-3","article-title":"Low level of plasminogen increases risk for mortality in COVID-19 patients","volume":"12","author":"Pacifici","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1111\/jth.15327","article-title":"Biomarkers of coagulation, endothelial function, and fibrinolysis in critically ill patients with COVID-19: A single-center prospective longitudinal study","volume":"19","author":"Juneja","year":"2021","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"111471","DOI":"10.1016\/j.mce.2021.111471","article-title":"Plasmin generates vasoinhibin-like peptides by cleaving prolactin and placental lactogen","volume":"538","author":"Friedrich","year":"2021","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1213\/ANE.0000000000003341","article-title":"Harmful or physiologic: Diagnosing fibrinolysis shutdown in a trauma cohort with rotational thromboelastometry","volume":"127","author":"Acuna","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1097\/SHK.0000000000001635","article-title":"Fibrinolysis shutdown and thrombosis in a COVID-19 ICU","volume":"55","author":"Auld","year":"2021","journal-title":"Shock"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1515\/cclm-2020-0188","article-title":"Prominent changes in blood coagulation of patients with SARS-CoV-2 infection","volume":"58","author":"Han","year":"2020","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1146\/annurev-physiol-021317-121143","article-title":"Epithelial Na(+) channel regulation by extracellular and intracellular factors","volume":"80","author":"Kleyman","year":"2018","journal-title":"Annu. Rev. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"F1488","DOI":"10.1152\/ajprenal.00439.2005","article-title":"Furin cleavage activates the epithelial Na+ channel by relieving Na+ self-inhibition","volume":"290","author":"Sheng","year":"2006","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"18111","DOI":"10.1074\/jbc.C400080200","article-title":"Epithelial sodium channels are activated by furin-dependent proteolysis","volume":"279","author":"Hughey","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1085\/jgp.200709781","article-title":"A segment of gamma ENaC mediates elastase activation of Na+ transport","volume":"130","author":"Adebamiro","year":"2007","journal-title":"J. Gen. Physiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"30073","DOI":"10.1074\/jbc.M111.338574","article-title":"Cathepsin B is secreted apically from Xenopus 2F3 cells and cleaves the epithelial sodium channel (ENaC) to increase its activity","volume":"287","author":"Alli","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e201912525","DOI":"10.1085\/jgp.201912525","article-title":"Prostaglandin E2 stimulates the epithelial sodium channel (ENaC) in cultured mouse cortical collecting duct cells in an autocrine manner","volume":"152","author":"Mansley","year":"2020","journal-title":"J. Gen. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1111\/bph.15038","article-title":"Plasmin improves blood-gas barrier function in oedematous lungs by cleaving epithelial sodium channels","volume":"177","author":"Zhao","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"L430","DOI":"10.1152\/ajplung.00499.2020","article-title":"SARS-CoV-2 may hijack GPCR signaling pathways to dysregulate lung ion and fluid transport","volume":"320","author":"Kuebler","year":"2021","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1085\/jgp.201110763","article-title":"Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the \u03b3 subunit of the human epithelial sodium channel","volume":"140","author":"Haerteis","year":"2012","journal-title":"J. Gen. Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41580-021-00418-x","article-title":"Mechanisms of SARS-CoV-2 entry into cells","volume":"23","author":"Jackson","year":"2022","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1161\/01.CIR.87.6.1969","article-title":"Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function","volume":"87","author":"Ridker","year":"1993","journal-title":"Circulation"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"L325","DOI":"10.1152\/ajplung.00189.2020","article-title":"Disequilibrium between the classic renin-angiotensin system and its opposing arm in SARS-CoV-2-related lung injury","volume":"319","author":"Sarzani","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0049-3848(02)00056-7","article-title":"L-158,809 and (D-Ala(7))-angiotensin I\/II (1-7) decrease PAI-1 release from human umbilical vein endothelial cells","volume":"105","author":"Yoshida","year":"2002","journal-title":"Thromb. Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1136\/postgradmedj-2020-137935","article-title":"ACE2 and COVID-19 and the resulting ARDS","volume":"96","author":"Zhang","year":"2020","journal-title":"Postgrad. Med. J."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1172\/JCI117809","article-title":"Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells. A potential link between the renin-angiotensin system and thrombosis","volume":"95","author":"Vaughan","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1046\/j.1523-1755.2000.00160.x","article-title":"Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo","volume":"58","author":"Nakamura","year":"2000","journal-title":"Kidney Int."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"L1020","DOI":"10.1152\/ajplung.00097.2020","article-title":"COVID-19 infection and mortality: A physiologist\u2019s perspective enlightening clinical features and plausible interventional strategies","volume":"318","author":"Abassi","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"e2011122","DOI":"10.1001\/jamanetworkopen.2020.11122","article-title":"Assessment of hypokalemia and clinical characteristics in patients with coronavirus disease 2019 in Wenzhou, China","volume":"3","author":"Chen","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"e20201129","DOI":"10.1084\/jem.20201129","article-title":"SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology","volume":"217","author":"Veras","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e20201012","DOI":"10.1084\/jem.20201012","article-title":"Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19","volume":"217","author":"Radermecker","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e20200652","DOI":"10.1084\/jem.20200652","article-title":"Targeting potential drivers of COVID-19: Neutrophil extracellular traps","volume":"217","author":"Barnes","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"14270","DOI":"10.1096\/fj.201901363RRR","article-title":"DNA-bound elastase of neutrophil extracellular traps degrades plasminogen, reduces plasmin formation, and decreases fibrinolysis: Proof of concept in septic shock plasma","volume":"33","author":"Helms","year":"2019","journal-title":"FASEB J."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1016\/S2213-2600(20)30418-5","article-title":"Human recombinant soluble ACE2 in severe COVID-19","volume":"8","author":"Zoufaly","year":"2020","journal-title":"Lancet. Respir. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.kint.2020.04.009","article-title":"Blockade of SARS-CoV-2 infection by recombinant soluble ACE2","volume":"97","author":"Drueke","year":"2020","journal-title":"Kidney Int."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/hr.2014.49","article-title":"Role of angiotensin-converting enzyme 2\/angiotensin-(1-7)\/Mas axis in the hypotensive effect of azilsartan","volume":"37","author":"Iwanami","year":"2014","journal-title":"Hypertens. Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/j.cell.2020.04.004","article-title":"Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2","volume":"181","author":"Monteil","year":"2020","journal-title":"Cell"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1055\/s-0041-1723086","article-title":"Potential of CRISPR\/Cas13 system in treatment and diagnosis of COVID-19","volume":"8","author":"Khodavirdipour","year":"2021","journal-title":"Glob. Med. Genet."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"101642","DOI":"10.1016\/j.isci.2020.101642","article-title":"Furin: A potential therapeutic target for COVID-19","volume":"23","author":"Wu","year":"2020","journal-title":"iScience"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"103255","DOI":"10.1016\/j.ebiom.2021.103255","article-title":"Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity","volume":"65","author":"Hoffmann","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1039\/D0SC05064D","article-title":"Molecular mechanism of inhibiting the SARS-CoV-2 cell entry facilitator TMPRSS2 with camostat and nafamostat","volume":"12","author":"Hempel","year":"2021","journal-title":"Chem. Sci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1111\/jcpt.13646","article-title":"Incidence and risk factors for hyperkalaemia in patients treated for COVID-19 with nafamostat mesylate","volume":"47","author":"Kodama","year":"2022","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"209","DOI":"10.34172\/bi.2020.27","article-title":"Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial","volume":"10","author":"Ansarin","year":"2020","journal-title":"BioImpacts"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/s41586-022-04661-w","article-title":"A\ufeff TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic","volume":"605","author":"Shapira","year":"2022","journal-title":"Nature"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1080\/00325481.2020.1855921","article-title":"JAK-STAT pathway inhibition and their implications in COVID-19 therapy","volume":"133","author":"Satarker","year":"2021","journal-title":"Postgrad. Med."},{"key":"ref_107","first-page":"694","article-title":"The effect of JAK1\/JAK2 inhibition in rheumatoid arthritis: Efficacy and safety of baricitinib","volume":"37","author":"Choy","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1080\/17476348.2022.2114899","article-title":"Therapeutic and anti-inflammatory effects of baricitinib on mortality, ICU transfer, clinical improvement, and CRS-related laboratory parameters of hospitalized patients with moderate to severe COVID-19 pneumonia: A systematic review and meta-analysis","volume":"16","author":"Ghojazadeh","year":"2022","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1016\/S2213-2600(21)00331-3","article-title":"Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): A randomised, double-blind, parallel-group, placebo-controlled phase 3 trial","volume":"9","author":"Marconi","year":"2021","journal-title":"Lancet. Respir. Med."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e002838","DOI":"10.1136\/jitc-2021-002838","article-title":"JAK inhibitors and COVID-19","volume":"10","author":"Levy","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Gudowska-Sawczuk, M., and Mroczko, B. (2022). The role of nuclear factor kappa B (NF-\u03baB) in development and treatment of COVID-19: Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23095283"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1021\/acsabm.1c00874","article-title":"Nanocurcumin potently inhibits SARS-CoV-2 spike protein-induced cytokine storm by deactivation of MAPK\/NF-\u03baB signaling in epithelial cells","volume":"5","author":"Sharma","year":"2022","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1552127","DOI":"10.1155\/2021\/1552127","article-title":"Curcumin ameliorates white matter injury after ischemic stroke by inhibiting microglia\/macrophage pyroptosis through NF-\u03baB suppression and NLRP3 inflammasome inhibition","volume":"2021","author":"Ran","year":"2021","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"116116","DOI":"10.1016\/j.taap.2022.116116","article-title":"Curcumin intervention during progressive fibrosis controls inflammatory cytokines and the fibrinolytic system in pulmonary fibrosis","volume":"449","author":"Barki","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1002\/ptr.6738","article-title":"Potential effects of curcumin in the treatment of COVID-19 infection","volume":"34","author":"Zahedipour","year":"2020","journal-title":"Phytother. Res."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/578\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:01:12Z","timestamp":1760122872000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/4\/578"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,23]]},"references-count":115,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["biom13040578"],"URL":"https:\/\/doi.org\/10.3390\/biom13040578","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2023,3,23]]}}}