{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T08:59:40Z","timestamp":1789808380955,"version":"4.0.1"},"reference-count":183,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,5,29]],"date-time":"2021-05-29T00:00:00Z","timestamp":1622246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"This study was supported by the Borders and Regions Airways Training Hub project (BREATH; INT-VA\/045) funded by the European Union (EU), under the INTERREG VA Programme, managed by the Special EU Programmes Body.","award":["INT-VA\/045"],"award-info":[{"award-number":["INT-VA\/045"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to persistent inflammation, infection and dysregulated protease activity. Although neutrophilic serine proteases, particularly neutrophil elastase, have been implicated in the propagation of inflammation and local tissue destruction, it is likely that the serine TLPs also contribute to various disease-relevant processes given the roles that a number of these enzymes play in the activation of both the epithelial sodium channel (ENaC) and protease-activated receptor 2 (PAR2). More recently, significant attention has focused on the activation of viruses such as SARS-CoV-2 by host TLPs. The purpose of this review was to highlight key TLPs linked to the activation of ENaC and PAR2 and their association with airway dehydration and inflammatory signalling pathways, respectively. The role of TLPs in viral infectivity will also be discussed in the context of the inhibition of TLP activities and the potential of these proteases as therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms22115817","type":"journal-article","created":{"date-parts":[[2021,5,31]],"date-time":"2021-05-31T00:22:15Z","timestamp":1622420535000},"page":"5817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases"],"prefix":"10.3390","volume":"22","author":[{"given":"Emma L.","family":"Carroll","sequence":"first","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariarca","family":"Bailo","sequence":"additional","affiliation":[{"name":"Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8599-5198","authenticated-orcid":false,"given":"James A.","family":"Reihill","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5980-3612","authenticated-orcid":false,"given":"Anne","family":"Crilly","sequence":"additional","affiliation":[{"name":"Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Lockhart","sequence":"additional","affiliation":[{"name":"Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary J.","family":"Litherland","sequence":"additional","affiliation":[{"name":"Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3150-1150","authenticated-orcid":false,"given":"Fionnuala T.","family":"Lundy","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorcan P.","family":"McGarvey","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Hollywood","sequence":"additional","affiliation":[{"name":"Smooth Muscle Research Centre, Dundalk Institute of Technology, A91 HRK2 Dundalk, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1923-0610","authenticated-orcid":false,"given":"S. Lorraine","family":"Martin","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Queen\u2019s University, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrm858","article-title":"Protease degradomics: A new challenge for proteomics","volume":"3","author":"Overall","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.mam.2008.04.003","article-title":"Protease proteomics: Revealing protease in vivo functions using systems biology approaches","volume":"29","author":"Doucet","year":"2008","journal-title":"Mol. Asp. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1111\/j.1476-5381.2009.00448.x","article-title":"Proteases and antiproteases in chronic neutrophilic lung disease\u2014Relevance to drug discovery","volume":"158","author":"Greene","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1136\/thx.48.5.560","article-title":"New perspectives on basic mechanisms in lung disease. 6. Proteinase imbalance: Its role in lung disease","volume":"48","author":"Tetley","year":"1993","journal-title":"Thorax"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1501200","DOI":"10.1183\/13993003.01200-2015","article-title":"Protean proteases: At the cutting edge of lung diseases","volume":"49","author":"Taggart","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chakraborti, S., Sarkar, J., Pramanik, P.K., and Chakraborti, T. (2017). Role of Proteases in Lung Disease: A Brief Overview. Proteases in Human Diseases, Springer Science and Business Media.","DOI":"10.1007\/978-981-10-3162-5_16"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1189\/jlb.3CE0215-057R","article-title":"Editorial: Neutrophil elastase and the lung: Is it degradation, repair, emphysema, or fibrosis? What tilts it left or right?","volume":"98","author":"Sallenave","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.chest.2017.03.056","article-title":"The role of neutrophil elastase inhibitors in lung diseases","volume":"152","author":"Polverino","year":"2017","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"L22","DOI":"10.1152\/ajplung.00163.2014","article-title":"Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition","volume":"308","author":"Hemmerling","year":"2015","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S216","DOI":"10.1513\/AnnalsATS.201806-368AW","article-title":"Emerging concepts and therapies for mucoobstructive lung disease","volume":"15","author":"Mall","year":"2018","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1006\/pupt.2001.0285","article-title":"Protease-activated Receptor-2 (PAR2) in the Airways","volume":"14","author":"Cocks","year":"2001","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.coviro.2017.03.018","article-title":"Airway proteases: An emerging drug target for influenza and other respiratory virus infections","volume":"24","author":"Laporte","year":"2017","journal-title":"Curr. Opin. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30433","DOI":"10.1074\/jbc.R800035200","article-title":"Proteases: Multifunctional enzymes in life and disease*","volume":"283","author":"Bond","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/iub.186","article-title":"Serine proteases","volume":"61","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"D227","DOI":"10.1093\/nar\/gkp971","article-title":"MEROPS: The peptidase database","volume":"38","author":"Rawlings","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Laskar, A., Rodger, E.J., Chatterjee, A., and Mandal, C. (2012). Modeling and structural analysis of PA clan serine proteases. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-256"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1007\/s00018-008-7565-9","article-title":"Serine peptidases: Classification, structure and function","volume":"65","author":"Page","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"B\u00f6ttcher-Friebertsh\u00e4user, E. (2018). Membrane-anchored serine proteases: Host cell factors in proteolytic activation of viral glycoproteins. Activation of Viruses by Host Proteases, Springer.","DOI":"10.1007\/978-3-319-75474-1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S52","DOI":"10.1164\/ajrccm.164.supplement_2.2106058","article-title":"Mast cell tryptases and airway remodeling","volume":"164","author":"Sommerhoff","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1111\/j.1742-4658.2006.05211.x","article-title":"Biology of mast cell tryptase","volume":"273","author":"Hallgren","year":"2006","journal-title":"FEBS J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"PA4017","DOI":"10.1183\/1393003.congress-2017.PA4017","article-title":"The development of a novel immunoassay for the quantification of active tryptase","volume":"50","author":"Ferguson","year":"2017","journal-title":"Monit. Airw. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Nimishakavi, S., Raymond, W.W., Gruenert, D.C., and Caughey, G.H. (2015). Divergent inhibitor susceptibility among airway lumen-accessible tryptic proteases. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141169"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18843","DOI":"10.1016\/S0021-9258(17)32244-5","article-title":"Prostasin is a novel human serine proteinase from seminal fluid. Purification, tissue distribution, and localization in prostate gland","volume":"269","author":"Yu","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21434","DOI":"10.1074\/jbc.M011423200","article-title":"Prostasin is a glycosylphosphatidylinositol-anchored active serine protease","volume":"276","author":"Chen","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"34864","DOI":"10.1074\/jbc.M805262200","article-title":"Structure of human prostasin, a target for the regulation of hypertension","volume":"283","author":"Rickert","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.bbrc.2004.09.123","article-title":"Biochemical characterization of prostasin, a channel activating protease","volume":"324","author":"Shipway","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"L657","DOI":"10.1152\/ajplung.00509.2016","article-title":"Human airway trypsin-like protease, a serine protease involved in respiratory diseases","volume":"312","author":"Menou","year":"2017","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1165\/ajrcmb.16.3.9070615","article-title":"Purification, characterization, and localization of a novel trypsin-like protease found in the human airway","volume":"16","author":"Yasuoka","year":"1997","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s004180000243","article-title":"Localization of human airway trypsin-like protease in the airway: An immunohistochemical study","volume":"115","author":"Takahashi","year":"2001","journal-title":"Histochem. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10016","DOI":"10.1128\/JVI.00239-10","article-title":"TMPRSS2 and TMPRSS4 facilitate tryp-sin-independent spread of influenza virus in Caco-2 cells","volume":"84","author":"Bertram","year":"2010","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1158\/2159-8290.CD-20-0451","article-title":"TMPRSS2 and COVID-19: Serendipity or opportunity for intervention?","volume":"10","author":"Stopsack","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1128\/MCB.26.3.965-975.2006","article-title":"Phenotypic analysis of mice lacking the Tmprss2-encoded protease","volume":"26","author":"Kim","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"26773","DOI":"10.1074\/jbc.M304282200","article-title":"The activation of matriptase requires its noncatalytic domains, serine protease domain, and its cognate inhibitor","volume":"278","author":"Oberst","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"C932","DOI":"10.1152\/ajpcell.00497.2004","article-title":"Simultaneous activation and hepatocyte growth factor activator inhibitor 1-mediated inhibition of matriptase induced at activation foci in human mammary epithelial cells","volume":"288","author":"Lee","year":"2005","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"C462","DOI":"10.1152\/ajpcell.00076.2005","article-title":"HAI-1 regulates activation and expression of matriptase, a membrane-bound serine protease","volume":"289","author":"Oberst","year":"2005","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1074\/jbc.M109.055640","article-title":"Matriptase activation, an early cellular response to acidosis","volume":"285","author":"Tseng","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tseng, C.-C., Jia, B., Barndt, R., Gu, Y., Chen, C.-Y., Tseng, I.-C., Su, S.-F., Wang, J.-K., Johnson, M.D., and Lin, C.-Y. (2017). Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183507"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/jcp.21115","article-title":"Co-localization of the channel activating protease prostasin\/(CAP1\/PRSS8) with its candidate activator, matriptase","volume":"213","author":"List","year":"2007","journal-title":"J. Cell. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1152\/physrev.1997.77.2.359","article-title":"Epithelial sodium channels: Function, structure, and regulation","volume":"77","author":"Garty","year":"1997","journal-title":"Physiol. Rev."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1164\/ajrccm.150.1.8025763","article-title":"Human airway ion transport. Part one","volume":"150","author":"Boucher","year":"1994","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00424-010-0827-z","article-title":"Regulation of the epithelial Na+ channel and airway surface liquid volume by serine proteases","volume":"460","author":"Gaillard","year":"2010","journal-title":"Eur. J. Physiol."},{"key":"ref_42","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_43","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.gene.2015.12.061","article-title":"Epithelial sodium channel (ENaC) family: Phylogeny, structure\u2013function, tissue distribution, and associated inherited diseases","volume":"579","author":"Hanukoglu","year":"2016","journal-title":"Gene"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1111\/febs.13840","article-title":"ASIC and ENaC type sodium channels: Conformational states and the structures of the ion selectivity filters","volume":"284","author":"Hanukoglu","year":"2016","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1111\/bph.13533","article-title":"The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na+channel (ENaC): IUPHAR Review 19","volume":"173","author":"Boscardin","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Noreng, S., Bharadwaj, A., Posert, R., Yoshioka, C., and Baconguis, I. (2018). Structure of the human epithelial sodium channel by cryo-electron microscopy. eLife, 7.","DOI":"10.7554\/eLife.39340"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1681\/ASN.2008020225","article-title":"Mechanisms of ENaC regulation and clinical implications","volume":"19","author":"Bhalla","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_48","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. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4928","DOI":"10.1074\/jbc.M117.819367","article-title":"Conserved cysteines in the finger domain of the epithelial Na+ channel alpha and gamma subunits are proximal to the dynamic finger-thumb domain interface","volume":"293","author":"Blobner","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"20447","DOI":"10.1074\/jbc.R800083200","article-title":"ENaC at the cutting edge: Regulation of epithelial sodium channels by proteases","volume":"284","author":"Kleyman","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1681\/ASN.2014060618","article-title":"Cutting it out: ENaC processing in the human nephron","volume":"26","author":"Ray","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00441-012-1439-z","article-title":"Proteases, cystic fibrosis and the epithelial sodium channel (ENaC)","volume":"351","author":"Thibodeau","year":"2012","journal-title":"Cell Tissue Res."},{"key":"ref_53","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_Kleymanetal","volume":"80","author":"Kleyman","year":"2018","journal-title":"Annu. Rev. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"190C","DOI":"10.1152\/ajpcell.00342.2003","article-title":"Serine protease activation of near-silent epithelial Na+ channels","volume":"286","author":"Caldwell","year":"2003","journal-title":"AJP Cell Physiol."},{"key":"ref_55","first-page":"607","article-title":"An epithelial serine protease activates the amiloride-sensitive sodium channel","volume":"389","author":"Vallet","year":"1997","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1681\/ASN.V115828","article-title":"Activation of the amiloride-sensitive epithelial sodium channel by the serine protease mCAP1 expressed in a mouse cortical collecting duct cell line","volume":"11","author":"Vuagniaux","year":"2000","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1085\/jgp.20028598","article-title":"Synergistic activation of ENaC by three membrane-bound channel-activating serine proteases (mCAP1, mCAP2, and mCAP3) and serum- and glucocorticoid-regulated kinase (Sgk1) in Xenopus Oocytes","volume":"20","author":"Vuagniaux","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1056\/NEJMra1813799","article-title":"Muco-obstructive lung diseases","volume":"380","author":"Boucher","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/mi.2016.63","article-title":"Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease","volume":"10","author":"Grubb","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1165\/rcmb.2006-0082SF","article-title":"Effective mucus clearance is essential for respiratory health","volume":"35","author":"Randell","year":"2006","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1056\/NEJMra0910061","article-title":"Airway mucus function and dysfunction","volume":"363","author":"Fahy","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2147\/COPD.S38938","article-title":"Clinical issues of mucus accumulation in COPD","volume":"9","author":"Kim","year":"2014","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_63","unstructured":"Mall, M. (2016). Unplugging mucus in cystic fibrosis and chronic obstructive pulmonary disease. Ann. Am. Thorac. Soc., 13."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/cpf.12085","article-title":"Mucociliary clearance: Pathophysiological aspects","volume":"34","author":"Munkholm","year":"2014","journal-title":"Clin. Physiol. Funct. Imaging"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.chest.2017.11.008","article-title":"Mucins, mucus, and goblet cells","volume":"154","author":"Ma","year":"2018","journal-title":"Chest"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1146\/annurev.physiol.70.113006.100702","article-title":"Structure and function of the polymeric mucins in airways mucus","volume":"70","author":"Thornton","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1378\/chest.08-0412","article-title":"Mucins, mucus, and sputum","volume":"135","author":"Voynow","year":"2009","journal-title":"Chest"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ni.3045","article-title":"Respiratory epithelial cells orchestrate pulmonary innate immunity","volume":"16","author":"Whitsett","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"L97","DOI":"10.1152\/ajplung.00303.2011","article-title":"Activity and inhibition of prostasin and matriptase on apical and basolateral surfaces of human airway epithelial cells","volume":"303","author":"Nimishakavi","year":"2012","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"L928","DOI":"10.1152\/ajplung.00160.2004","article-title":"Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME\/CF15 cells, a cystic fibrosis airway epithelial cell line","volume":"287","author":"Tong","year":"2004","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1164\/rccm.201511-2216OC","article-title":"Inhibition of protease\u2013epithelial sodium channel signaling improves mucociliary function in cystic fibrosis airways","volume":"194","author":"Reihill","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_72","first-page":"PA4933","article-title":"Detection and inhibition of ENaC-activating proteases associated with airway dehydration in COPD","volume":"50","author":"Martin","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0014-5793(96)01414-7","article-title":"Inhibition of epithelial Na+ currents by intracellular domains of the cystic fibrosis transmembrane conductance regulator","volume":"400","author":"Kunzelmann","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1172\/JCI112708","article-title":"Na+ transport in cystic fibrosis respiratory epithelia. Abnormal basal rate and response to adenylate cyclase activation","volume":"78","author":"Boucher","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"4377","DOI":"10.1113\/jphysiol.2012.240861","article-title":"Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?","volume":"591","author":"Hobbs","year":"2013","journal-title":"J. Physiol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.1007\/s00018-015-1946-7","article-title":"Airway hydration and COPD","volume":"72","author":"Ghosh","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Seys, L.J.M., Verhamme, F.M., Dupont, L.L., Desauter, E., Duerr, J., Agircan, A.S., Conickx, G., Joos, G.F., Brusselle, G.G., and Mall, M.A. (2015). Airway surface dehydration aggravates cigarette smoke-induced hallmarks of COPD in mice. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0129897"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, G., Xu, Z., Wang, R., Al-Hijji, M., Salit, J., Strulovici-Barel, Y., Tilley, A., Mezey, J.G., and Crystal, R.G. (2012). Genes associated with MUC5AC expression in small airway epithelium of human smokers and non-smokers. BMC Med. Genom., 5.","DOI":"10.1186\/1755-8794-5-21"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1042\/BST0370877","article-title":"Regulation of mucin expression in respiratory diseases","volume":"37","author":"Turner","year":"2009","journal-title":"Biochem. Soc. Trans."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev.physiol.70.113006.100441","article-title":"Regulation of airway mucin gene expression","volume":"70","author":"Thai","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1165\/rcmb.2003-0199OC","article-title":"Human airway trypsin-like protease increases mucin gene expression in airway epithelial cells","volume":"30","author":"Chokki","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1124\/pr.54.2.203","article-title":"International union of pharmacology. XXVIII. Proteinase-activated receptors","volume":"54","author":"Hollenberg","year":"2002","journal-title":"Pharmacol. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/0092-8674(91)90261-V","article-title":"Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation","volume":"64","author":"Vu","year":"1991","journal-title":"Cell"},{"key":"ref_84","first-page":"502","article-title":"Protease-activated receptor 3 is a second thrombin receptor in humans","volume":"386","author":"Ishihara","year":"1997","journal-title":"Nat. Cell Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"6642","DOI":"10.1073\/pnas.95.12.6642","article-title":"Cloning and characterization of human prote-ase-activated receptor 4","volume":"95","author":"Xu","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"9208","DOI":"10.1073\/pnas.91.20.9208","article-title":"Molecular cloning of a potential proteinase activated receptor","volume":"91","author":"Nystedt","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","first-page":"84","article-title":"Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2","volume":"232","author":"Nystedt","year":"1995","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4819","DOI":"10.1073\/pnas.011099798","article-title":"How activated receptors couple to G proteins","volume":"98","author":"Hamm","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1124\/mol.109.055509","article-title":"Agonist-biased signaling via proteinase activated receptor-2: Differential activation of calcium and mitogen-activated protein kinase pathways","volume":"76","author":"Ramachandran","year":"2009","journal-title":"Mol Pharmacol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/j.pharmthera.2011.01.003","article-title":"Structure, function and pathophysiology of protease activated receptors","volume":"130","author":"Adams","year":"2011","journal-title":"Pharmacol. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"5950","DOI":"10.1074\/jbc.270.11.5950","article-title":"The mouse proteinase-activated receptor-2 cDNA and gene","volume":"270","author":"Nystedt","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1074\/jbc.272.7.4043","article-title":"Interactions of mast cell tryptase with thrombin receptors and PAR-2","volume":"272","author":"Molino","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1111\/bph.12544","article-title":"Biased signalling and proteinase-activated receptors (PARs): Targeting inflammatory disease","volume":"171","author":"Hollenberg","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"22003","DOI":"10.1074\/jbc.271.36.22003","article-title":"Mechanisms of desensitization and resensitization of proteinase-activated receptor-2","volume":"271","author":"Khitin","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1038\/sj.bjp.0706204","article-title":"The role of intracellular Ca2+ in the regulation of proteinase-activated receptor-2 mediated nuclear factor kappa B signalling in keratinocytes","volume":"145","author":"Macfarlane","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"9151","DOI":"10.1073\/pnas.92.20.9151","article-title":"Evidence for the presence of a protease-activated receptor distinct from the thrombin receptor in human keratinocytes","volume":"92","author":"Santulli","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.pharmthera.2007.04.002","article-title":"A novel therapeutic target in various lung diseases: Airway proteases and protease-activated receptors","volume":"115","author":"Sokolova","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"24638","DOI":"10.1074\/jbc.M110.201988","article-title":"Neutrophil elastase acts as a biased agonist for proteinase-activated receptor-2 (PAR2)","volume":"286","author":"Ramachandran","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1186\/1478-811X-11-86","article-title":"Proteinase-activated receptors (PARs)\u2014Focus on re-ceptor-receptor-interactions and their physiological and pathophysiological impact","volume":"11","author":"Gieseler","year":"2013","journal-title":"Cell Commun. Signal."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Zhao, P., Metcalf, M., and Bunnett, N.W. (2015). Corrigendum: Biased Signaling of protease-activated receptors. Front. Endocrinol., 5.","DOI":"10.3389\/fendo.2014.00228"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1476-5381.2010.00705.x","article-title":"Signal transduction by protease-activated receptors","volume":"160","author":"Soh","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1124\/mol.104.006072","article-title":"Multiple independent functions of arrestins in the regulation of protease-activated receptor-2 signaling and trafficking","volume":"67","author":"Stalheim","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"S298","DOI":"10.1038\/sj.bjp.0707508","article-title":"Beta-arrestins and heterotrimeric G-proteins: Collaborators and competitors in signal transduction","volume":"153","author":"Defea","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"16076","DOI":"10.1074\/jbc.M500109200","article-title":"c-Cbl Mediates ubiquitination, degradation, and down-regulation of human protease-activated receptor 2","volume":"280","author":"Jacob","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_105","first-page":"130","article-title":"The multiple facets of alpha-1-antitrypsin","volume":"3","author":"Stockley","year":"2015","journal-title":"Ann. Transl. Med."},{"key":"ref_106","first-page":"156","article-title":"A protective role for protease-activated receptors in the airways","volume":"398","author":"Cocks","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.bbadis.2010.12.014","article-title":"Mast cells and inflammation","volume":"1822","author":"Theoharides","year":"2012","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/S0006-2952(03)00292-2","article-title":"Proteinase-activated receptor-2 mediates hyperresponsiveness in isolated guinea pig bronchi","volume":"66","author":"Barrios","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1152\/jappl.2001.91.3.1372","article-title":"Tryptase and agonists of PAR-2 induce the pro-liferation of human airway smooth muscle cells","volume":"91","author":"Berger","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"L193","DOI":"10.1152\/ajplung.2000.278.1.L193","article-title":"Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2","volume":"278","author":"Akers","year":"2000","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12964-018-0269-3","article-title":"Mast cells and mast cell tryptase enhance migration of human lung fibroblasts through protease-activated receptor 2","volume":"16","author":"Bagher","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1161\/01.ATV.0000258862.61067.14","article-title":"Membrane-type serine protease-1\/matriptase induces interleukin-6 and -8 in endothelial cells by activation of protease-activated receptor-2: Potential implications in atherosclerosis","volume":"27","author":"Seitz","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.devcel.2009.11.014","article-title":"Local protease signaling contributes to neural tube closure in the mouse embryo","volume":"18","author":"Camerer","year":"2010","journal-title":"Dev. Cell"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1083\/jcb.201709118","article-title":"Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia","volume":"217","author":"Schepis","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(11)60052-4","article-title":"Idiopathic pulmonary fibrosis","volume":"378","author":"King","year":"2011","journal-title":"Lancet"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1164\/rccm.201502-0299OC","article-title":"Membrane-anchored serine protease matriptase is a trigger of pulmonary fibrogenesis","volume":"193","author":"Bardou","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/ncomms1162","article-title":"PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1\/Prss8 expression in mouse skin","volume":"2","author":"Frateschi","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"L385","DOI":"10.1152\/ajplung.00098.2005","article-title":"Human airway trypsin-like protease stim-ulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway","volume":"290","author":"Matsushima","year":"2006","journal-title":"Am. J. Physiol. Lung. Cell. Mol. Physiol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.abb.2013.02.013","article-title":"Human airway trypsin-like protease induces mucin5AC hypersecretion via a protease-activated receptor 2-mediated pathway in human airway epithelial cells","volume":"535","author":"Liu","year":"2013","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.abb.2019.01.019","article-title":"Human airway trypsin-like protease enhances interleukin-8 synthesis in bronchial epithelial cells by activating protease-activated receptor 2","volume":"664","author":"Miki","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3577","DOI":"10.4049\/jimmunol.168.7.3577","article-title":"Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2release from human respiratory epithelial cells","volume":"168","author":"Asokananthan","year":"2002","journal-title":"J. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1136\/thorax.57.2.146","article-title":"Expression of protease activated receptor-2 (PAR-2) in central airways of smokers and non-smokers","volume":"57","author":"Miotto","year":"2002","journal-title":"Thorax"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1067\/mai.2001.119025","article-title":"Protease-activated receptors in human airways: Up-regulation of PAR-2 in respiratory epithelium from patients with asthma","volume":"108","author":"Knight","year":"2001","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.regpep.2007.08.002","article-title":"Signal transduction for formation\/release of interleukin-8 caused by a PAR2-activating peptide in human lung epithelial cells","volume":"145","author":"Moriyuki","year":"2008","journal-title":"Regul. Pept."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.ejphar.2005.12.051","article-title":"The protease-activated receptor2 (PAR2)-prostaglandin E2-prostanoid EP receptor axis: A potential bronchoprotec-tive unit in the respiratory tract?","volume":"533","author":"Henry","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/sj.bjp.0706150","article-title":"Stimulation of protease-activated receptor-2 inhibits airway eosinophilia, hyperresponsiveness and bronchoconstriction in a murine model of allergic inflammation","volume":"144","author":"Henry","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.bcp.2005.10.016","article-title":"A protective role for proteinase activated receptor 2 in airways of lipopolysaccharide-treated rats","volume":"71","author":"Morello","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4103\/JMAU.JMAU_55_18","article-title":"Effect of protease-activated receptor-2-activating peptide on guinea pig airway resistance and isolated tracheal strips","volume":"8","author":"Hagras","year":"2020","journal-title":"J. Microsc. Ultrastruct."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1183\/09031936.00202311","article-title":"Viral infections trigger exacerbations of cystic fibrosis in adults and children","volume":"40","author":"Wark","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.jaci.2010.04.021","article-title":"The role of viruses in acute exacerbations of asthma","volume":"125","author":"Jackson","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"180063","DOI":"10.1183\/16000617.0063-2018","article-title":"Respiratory viral infection: A potential \u201cmissing link\u201d in the pathogenesis of COPD","volume":"28","author":"Linden","year":"2019","journal-title":"Eur. Respir. Rev."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Izaguirre, G. (2019). The proteolytic regulation of virus cell entry by furin and other proprotein convertases. Viruses, 11.","DOI":"10.3390\/v11090837"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.tim.2018.05.013","article-title":"Influenza Virus","volume":"26","author":"Hutchinson","year":"2018","journal-title":"Trends Microbiol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"020421","DOI":"10.7189\/jogh.09.020421","article-title":"Global mortality associated with seasonal influenza epidemics: New burden estimates and predictors from the GLaMOR Project","volume":"9","author":"Paget","year":"2019","journal-title":"J. Glob. Health"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"9896","DOI":"10.1128\/JVI.01118-06","article-title":"Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium","volume":"80","author":"Matrosovich","year":"2006","journal-title":"J. Virol."},{"key":"ref_136","first-page":"1554","article-title":"Inhibition of influenza virus infection in human airway cell cultures by an antisense peptide-conjugated morpholino oligomer targeting the hemagglutinin-activating protease TMPRSS2","volume":"85","author":"Stein","year":"2010","journal-title":"J. Virol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"10579","DOI":"10.1128\/JVI.00306-12","article-title":"Cleavage activation of the human-adapted influenza virus subtypes by matriptase reveals both subtype and strain specificities","volume":"86","author":"Hamilton","year":"2012","journal-title":"J. Virol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1128\/JVI.03005-12","article-title":"Matriptase proteolytically activates influenza virus and promotes multicycle replication in the human airway epithelium","volume":"87","author":"Beaulieu","year":"2013","journal-title":"J. Virol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"11388","DOI":"10.1074\/jbc.RA120.012635","article-title":"Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways","volume":"295","author":"Harbig","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1007\/s00108-019-00671-5","article-title":"Coronaviruses as the cause of respiratory infections","volume":"60","author":"Corman","year":"2019","journal-title":"Internist"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev-med-051215-031152","article-title":"Middle east respiratory syndrome: Emergence of a pathogenic human coronavirus","volume":"68","author":"Fehr","year":"2017","journal-title":"Annu. Rev. Med."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/S0140-6736(20)30154-9","article-title":"A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster","volume":"395","author":"Chan","year":"2020","journal-title":"Lancet"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Fraser, E. (2020). Long term respiratory complications of covid-19. BMJ, 370.","DOI":"10.1136\/bmj.m3001"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"12658","DOI":"10.1128\/JVI.01542-10","article-title":"Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2","volume":"84","author":"Matsuyama","year":"2010","journal-title":"J. Virol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"12552","DOI":"10.1128\/JVI.01890-13","article-title":"Middle east respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2","volume":"87","author":"Shirato","year":"2013","journal-title":"J. Virol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1128\/JVI.05300-11","article-title":"Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease","volume":"85","author":"Bertram","year":"2011","journal-title":"J. Virol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/978-1-0716-0211-9_3","article-title":"Biochemical characterization of Middle East respiratory syndrome coronavirus spike protein proteo-lytic processing","volume":"2099","author":"Whittaker","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_148","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_149","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtm.2020.05.013","article-title":"Airways expression of SARS-CoV-2 receptor, ACE2, and TMPRSS2 Is lower in children than adults and increases with smoking and COPD","volume":"18","author":"Alabed","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"L408","DOI":"10.1152\/ajplung.00225.2020","article-title":"SARS-CoV-2 (COVID-19) and cystic fibrosis","volume":"319","author":"Stanton","year":"2020","journal-title":"Am. J. Physiol. Lung. Cell Mol. Physiol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"4751","DOI":"10.1021\/cr010170+","article-title":"Serpin structure, mechanism, and function","volume":"102","author":"Gettins","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/gb-2006-7-5-216","article-title":"An overview of the serpin superfamily","volume":"7","author":"Law","year":"2006","journal-title":"Genome Biol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.rmed.2011.02.002","article-title":"The discovery of \u03b11-antitrypsin and its role in health and disease","volume":"105","author":"Janciauskiene","year":"2011","journal-title":"Respir. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1165\/rcmb.2008-0015RC","article-title":"Alpha1-antitrypsin inhibits the activity of the matriptase catalytic domain in vitro","volume":"39","author":"Janciauskiene","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1165\/rcmb.2008-0384OC","article-title":"Alpha(1)-antitrypsin inhibits epithelial Na+ transport in vitro and in vivo","volume":"41","author":"Lazrak","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Azouz, N.P., Klingler, A.M., Callahan, V., Akhrymuk, I.V., Elez, K., Raich, L., Henry, B., Benoit, J., Benoit, S., and No\u00e9, F. (2020). Alpha 1 antitrypsin is an Inhibitor of the SARS-CoV-2-priming protease TMPRSS2. bioRxiv.","DOI":"10.1101\/2020.05.04.077826"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3389\/fphar.2018.00341","article-title":"The multifaceted effects of al-pha1-antitrypsin on neutrophil functions","volume":"9","author":"Janciauskiene","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1165\/rcmb.2013-0103OC","article-title":"High-density lipoproteins po-tentiate alpha1-antitrypsin therapy in elastase-induced pulmonary emphysema","volume":"51","author":"Moreno","year":"2014","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1038\/nm.2084","article-title":"Neutrophil elastase\u2013mediated degradation of IRS-1 accelerates lung tumor growth","volume":"16","author":"Houghton","year":"2010","journal-title":"Nat. Med."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1242\/jcs.079889","article-title":"Plasminogen activator inhibitor 1 is an intracellular inhibitor of furin proprotein convertase","volume":"124","author":"Bernot","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.cell.2015.01.040","article-title":"A serpin shapes the extracellular environment to prevent influenza A virus maturation","volume":"160","author":"Dittmann","year":"2015","journal-title":"Cell"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"L932","DOI":"10.1152\/ajplung.00437.2007","article-title":"Prostasin expression is regulated by airway surface liquid volume and is increased in cystic fibrosis","volume":"294","author":"Myerburg","year":"2008","journal-title":"Am. J. Physiol. Cell. Mol. Physiol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"5105","DOI":"10.1074\/jbc.RA118.007292","article-title":"Disulfide engineering of human Kunitz-type serine protease inhibitors enhances proteolytic stability and target affinity toward mesotrypsin","volume":"294","author":"Cohen","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"29495","DOI":"10.1074\/jbc.M801970200","article-title":"Potent inhibition and global co-localization implicate the trans-membrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity","volume":"283","author":"Szabo","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"8412","DOI":"10.1074\/jbc.M117.779256","article-title":"The crystal structure of a multidomain protease inhibitor (HAI-1) reveals the mechanism of its auto-inhibition","volume":"292","author":"Liu","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/jb\/mvr131","article-title":"Hepatocyte growth factor activator inhibitor type 1 inhibits protease activity and proteolytic activation of human airway trypsin-like protease","volume":"151","author":"Kato","year":"2011","journal-title":"J. Biochem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1038\/sj.onc.1209966","article-title":"Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development","volume":"26","author":"Szabo","year":"2006","journal-title":"Oncogene"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1085\/jgp.19.6.991","article-title":"Isolation from beef pancreas of crystalline trypsinogen trypsin, a trypsin inhibitor, and an inhibi-tor-trypsin compound","volume":"19","author":"Kunitz","year":"1936","journal-title":"J. Gen. Physiol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2174\/1389203033487180","article-title":"The bovine basic pancreatic trypsin inhibitor (kunitz inhibitor): A milestone protein","volume":"4","author":"Ascenzi","year":"2003","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.athoracsur.2007.05.015","article-title":"Aprotinin and anaphylaxis: Analysis of 12,403 exposures to aprotinin in cardiac surgery","volume":"84","author":"Dietrich","year":"2007","journal-title":"Ann. Thorac. Surg."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1056\/NEJMoa0802395","article-title":"A comparison of aprotinin and lysine ana-logues in high-risk cardiac surgery","volume":"358","author":"Fergusson","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1503\/cmaj.131582","article-title":"Regulatory decisions pertaining to aprotinin may be putting patients at risk","volume":"186","author":"Fergusson","year":"2014","journal-title":"Can. Med Assoc. J."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jtcvs.2012.07.018","article-title":"Putting the record straight on aprotinin as safe and effective: Results from a mixed treatment meta-analysis of trials of aprotinin","volume":"145","author":"Howell","year":"2013","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.antiviral.2011.07.014","article-title":"Aprotinin and similar protease inhibitors as drugs against influenza","volume":"92","author":"Zhirnov","year":"2011","journal-title":"Antivir. Res."},{"key":"ref_175","doi-asserted-by":"crossref","unstructured":"Bojkova, D., Bechtel, M., McLaughlin, K.M., McGreig, J.E., Klann, K., Bellinghausen, C., Rohde, G., Konigk, D., Braubach, P., and Ciesek, S. (2020). Aprotinin inhibits SARS-CoV-2 replication. Cells, 9.","DOI":"10.3390\/cells9112377"},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1021\/acs.oprd.0c00233","article-title":"Quest for a COVID-19 cure by repurposing small-molecule drugs: Mechanism of action, clinical development, synthesis at scale, and outlook for supply","volume":"24","author":"Hughes","year":"2020","journal-title":"Org. Process. Res. Dev."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.pupt.2015.07.001","article-title":"The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells","volume":"33","author":"Yamaya","year":"2015","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_178","first-page":"103255","article-title":"Camostat mesylate inhibits SARS-CoV-2 activation by TMPRSS2-related proteases and its metabolite GBPA exerts antiviral activity","volume":"5","author":"Hoffmann","year":"2020","journal-title":"bioRxiv"},{"key":"ref_179","doi-asserted-by":"crossref","unstructured":"Idda, M.L., Soru, D., and Floris, M. (2020). Overview of the First 6 months of clinical trials for COVID-19 pharmacotherapy: The most studied drugs. Front. Public Heal., 8.","DOI":"10.3389\/fpubh.2020.00497"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1124\/jpet.108.148155","article-title":"Camostat attenuates airway epi-thelial sodium channel function in vivo through the inhibition of a channel-activating protease","volume":"329","author":"Coote","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1182\/blood-2017-02-768218","article-title":"Identification of the integrin-binding site on coagulation factor VIIa required for proangiogenic PAR2 signaling","volume":"131","author":"Rothmeier","year":"2018","journal-title":"Blood"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"e00754-20","DOI":"10.1128\/AAC.00754-20","article-title":"Nafamostat mesylate blocks activation of SARS-CoV-2: New treatment option for COVID-19","volume":"64","author":"Hoffmann","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1164\/rccm.201604-0781ED","article-title":"A protease inhibitor tackles epithelial sodium channels in cystic fibrosis","volume":"194","author":"Schultz","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:10:16Z","timestamp":1760163016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,29]]},"references-count":183,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115817"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115817","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,29]]}}}