{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:17:23Z","timestamp":1791404243474,"version":"4.3.3"},"reference-count":88,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Airway inflammation plays a central role in bronchiectasis. Protease\u2013antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases\u2019 over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of \u03b11-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease\u2013antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.<\/jats:p>","DOI":"10.3390\/ijms22115996","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T15:58:44Z","timestamp":1622563124000},"page":"5996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Protease\u2013Antiprotease Imbalance in Bronchiectasis"],"prefix":"10.3390","volume":"22","author":[{"given":"Martina","family":"Oriano","sequence":"first","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Amati","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Gramegna","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"De Soyza","sequence":"additional","affiliation":[{"name":"Population and Health Science Institute, NIHR Biomedical Research Centre for Ageing & Freeman Hospital, Newcastle University, Newcastle NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7324-1217","authenticated-orcid":false,"given":"Marco","family":"Mantero","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriol","family":"Sibila","sequence":"additional","affiliation":[{"name":"Respiratory Department, Hospital Clinic, IDIBAPS, CIBERES, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0417-7607","authenticated-orcid":false,"given":"Sanjay H.","family":"Chotirmall","sequence":"additional","affiliation":[{"name":"Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Voza","sequence":"additional","affiliation":[{"name":"Emergency Department, IRCCS Humanitas Research Teaching Hospital, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-3920","authenticated-orcid":false,"given":"Paola","family":"Marchisio","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Paediatric Highly Intensive Care Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-9970","authenticated-orcid":false,"given":"Francesco","family":"Blasi","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-4531","authenticated-orcid":false,"given":"Stefano","family":"Aliberti","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1700629","DOI":"10.1183\/13993003.00629-2017","article-title":"European Respiratory Society guidelines for the management of adult bronchiectasis","volume":"50","author":"Polverino","year":"2017","journal-title":"Eur. Respir. J."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aliberti, S., Sotgiu, G., Lapi, F., Gramegna, A., Cricelli, C., and Blasi, F. (2020). Prevalence and incidence of bronchiectasis in Italy. BMC Pulm. Med., 20.","DOI":"10.1186\/s12890-020-1050-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1183\/13993003.01033-2015","article-title":"Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: A population-based cohort study","volume":"47","author":"Quint","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.rmed.2016.10.014","article-title":"Prevalence and incidence of bronchiectasis in Catalonia, Spain: A population-based study","volume":"121","author":"Monteagudo","year":"2016","journal-title":"Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1513\/AnnalsATS.201507-472OC","article-title":"Etiology of Non-Cystic Fibrosis Bronchiectasis in Adults and Its Correlation to Disease Severity","volume":"12","author":"Lonni","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1016\/S0140-6736(18)31767-7","article-title":"Advances in bronchiectasis: Endotyping, genetics, microbiome, and disease heterogeneity","volume":"392","author":"Flume","year":"2018","journal-title":"Lancet"},{"key":"ref_7","first-page":"6","article-title":"Inflammation: A two-edged sword\u2014The model of bronchiectasis","volume":"147","author":"Cole","year":"1986","journal-title":"Eur. J. Respir. Dis. Suppl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"190055","DOI":"10.1183\/16000617.0055-2019","article-title":"The biology of pulmonary exacerbations in bronchiectasis","volume":"28","author":"Amati","year":"2019","journal-title":"Eur. Respir. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Faverio, P., Stainer, A., Bonaiti, G., Zucchetti, S.C., Simonetta, E., Lapadula, G., Marruchella, A., Gori, A., Blasi, F., and Codecasa, L. (2016). Characterizing Non-Tuberculous Mycobacteria Infection in Bronchiectasis. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111913"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"197950","DOI":"10.1155\/2015\/197950","article-title":"Nontuberculous Mycobacteria in Noncystic Fibrosis Bronchiectasis","volume":"2015","author":"Bonaiti","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.ccm.2016.04.008","article-title":"Primary Ciliary Dyskinesia","volume":"37","author":"Knowles","year":"2016","journal-title":"Clin. Chest Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40248-018-0143-6","article-title":"Why, when and how to investigate primary ciliary dyskinesia in adult patients with bronchiectasis","volume":"13","author":"Contarini","year":"2018","journal-title":"Multidiscip. Respir. Med."},{"key":"ref_13","first-page":"S5","article-title":"Mucus obstruction and inflammation in early cystic fibrosis lung disease: Emerging role of the IL-1 signaling pathway","volume":"54","author":"Mall","year":"2019","journal-title":"Pediatr. Pulmonol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1002\/ppul.24599","article-title":"Bronchiectasis in common variable immunodeficiency: A systematic review and meta-analysis","volume":"55","author":"Ramzi","year":"2020","journal-title":"Pediatr. Pulmonol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41584-019-0275-x","article-title":"Mechanisms of lung disease development in rheumatoid arthritis","volume":"15","author":"Wang","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1900303","DOI":"10.1183\/13993003.00303-2019","article-title":"A point-of-care neutrophil elastase activity assay identifies bronchiectasis severity, airway infection and risk of exacerbation","volume":"53","author":"Shoemark","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2000769","DOI":"10.1183\/13993003.00769-2020","article-title":"Sputum Neutrophil Elastase associates with microbiota and P. aeruginosa in bronchiectasis","volume":"56","author":"Oriano","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2001702","DOI":"10.1183\/13993003.01702-2020","article-title":"Sputum neutrophil elastase in bronchiectasis: A Southern European cohort study","volume":"56","author":"Gramegna","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1038\/nprot.2008.63","article-title":"Measuring elastase, proteinase 3 and cathepsin G activities at the surface of human neutrophils with fluorescence resonance energy transfer substrates","volume":"3","author":"Korkmaz","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1136\/thx.2005.051979","article-title":"Matrix metalloproteinases in destructive pulmonary pathology","volume":"61","author":"Elkington","year":"2006","journal-title":"Thorax"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1164\/rccm.201605-1027OC","article-title":"Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis","volume":"195","author":"Chalmers","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Keir, H.R., Shoemark, A., Dicker, A.J., Perea, L., Pollock, J., Giam, Y.H., Suarez-Cuartin, G., Crichton, M.L., Lonergan, M., and Oriano, M. (2020). Neutrophil Extracellular Traps are Increased in Severe Bronchiectasis and Reduced by Long-Term Azithromycin Treatment. Lancet.","DOI":"10.2139\/ssrn.3678620"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1034\/j.1600-0757.2000.2240108.x","article-title":"Role of bacterial proteinases in matrix destruction and modulation of host responses","volume":"24","author":"Potempa","year":"2000","journal-title":"Periodontol. 2000"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1080\/21505594.2018.1489198","article-title":"Inhibition of Pseudomonas aeruginosa secreted virulence factors reduces lung inflammation in CF mice","volume":"9","author":"Sandri","year":"2018","journal-title":"Virulence"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"642503","DOI":"10.1155\/2015\/642503","article-title":"Neutrophilic Bronchial Inflammation Correlates with Clinical and Functional Findings in Patients with Noncystic Fibrosis Bronchiectasis","volume":"2015","author":"Dente","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1056\/NEJM198902093200606","article-title":"Tissue destruction by neutrophils","volume":"320","author":"Weiss","year":"1989","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1128\/IAI.00832-08","article-title":"Neutrophil Recruitment to the Lungs during Bacterial Pneumonia","volume":"77","author":"Craig","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1056\/NEJM198007033030109","article-title":"Release of Inflammatory Mediators from Stimulated Neutrophils","volume":"303","author":"Weissmann","year":"1980","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1159\/000345943","article-title":"Tissue-Specific Neutrophil Recruitment into the Lung, Liver, and Kidney","volume":"5","author":"Rossaint","year":"2013","journal-title":"J. Innate Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1183\/13993003.01899-2015","article-title":"Clinical phenotypes in adult patients with bronchiectasis","volume":"47","author":"Aliberti","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1164\/rccm.201203-0487OC","article-title":"Short- and Long-Term Antibiotic Treatment Reduces Airway and Systemic Inflammation in Non\u2013Cystic Fibrosis Bronchiectasis","volume":"186","author":"Chalmers","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Keir, H.R., Shoemark, A., Dicker, A.J., Perea, L., Pollock, J., Giam, Y.H., Suarez-Cuartin, G., Crichton, M.L., Lonergan, M., and Oriano, M. (2021). Neutrophil extracellular traps, disease severity, and antibiotic response in bronchiectasis: An international, observational, multicohort study. Lancet Respir. Med.","DOI":"10.1016\/S2213-2600(20)30504-X"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sibila, O., Perea, L., Cant\u00f3, E., Shoemark, A., Cassidy, D., Smith, A.H., Suarez-Cuartin, G., Rodrigo-Troyano, A., Keir, H.R., and Oriano, M. (2019). Antimicrobial peptides, disease severity and exacerbations in bronchiectasis. Thorax, thoraxjnl-2018-212895.","DOI":"10.1136\/thoraxjnl-2018-212895"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1183\/09031936.00069007","article-title":"Mucosal inflammation in idiopathic bronchiectasis: Cellular and molecular mechanisms","volume":"31","author":"Fuschillo","year":"2008","journal-title":"Eur. Respir. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1164\/ajrccm.164.9.2105083","article-title":"Bronchial inflammation and colonization in patients with clinically stable bronchiectasis","volume":"164","author":"Angrill","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106127","DOI":"10.1016\/j.rmed.2020.106127","article-title":"Role of inhaled corticosteroids in reducing exacerbations in bronchiectasis patients with blood eosinophilia pooled post-hoc analysis of 2 randomized clinical trials","volume":"172","author":"Posadas","year":"2020","journal-title":"Respir. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1016\/j.chest.2020.11.011","article-title":"A Cluster Analysis of Bronchiectasis Patients Based on the Airway Immune Profile","volume":"159","author":"Perea","year":"2020","journal-title":"Chest"},{"key":"ref_38","first-page":"681","article-title":"Repeteability of Circulating Eosinophil Measures and Inhaled Corticosteroids Effect in Bronchiectasis: A Post Hoc Analysis of a Randomized Clinical Trial","volume":"56","author":"Posadas","year":"2020","journal-title":"Arch. Bronconeumol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2002210","DOI":"10.1183\/13993003.02210-2020","article-title":"Blood eosinophils do not predict inhaled budesonide response in bronchiectasis","volume":"56","author":"Aliberti","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1901333","DOI":"10.1183\/13993003.01333-2019","article-title":"Anti-IL5 and anti-IL5R\u03b1 therapy for clinically significant bronchiectasis with eosinophilic endotype: A case series","volume":"55","author":"Rademacher","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"509","DOI":"10.4049\/jimmunol.172.1.509","article-title":"Neutrophil serine proteinases cleave bacterial flagellin, abrogating its host response-inducing activity","volume":"172","author":"Espinola","year":"2004","journal-title":"J. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Small, D.M., Brown, R.R., Doherty, D.F., Abladey, A., Zhou-Suckow, Z., Delaney, R.J., Kerrigan, L., Dougan, C.M., Borensztajn, K.S., and Holsinger, L. (2019). Targeting of Cathepsin S Reduces Cystic Fibrosis-like Lung Disease. Eur. Respir. J., 1801523.","DOI":"10.1183\/13993003.01523-2018"},{"key":"ref_43","unstructured":"Segal, A.W. (2007). Europe PMC Funders Group How Neutrophils Kill Microbes. Annu. Rev. Immunol., 2."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1124\/pr.110.002733","article-title":"Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases","volume":"62","author":"Korkmaz","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1203\/01.pdr.0000250043.90468.c2","article-title":"Cathepsin-G interferes with clearance of Pseudomonas aeruginosa from mouse lungs","volume":"61","author":"Sedor","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s12931-018-0883-z","article-title":"Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases","volume":"19","author":"Crisford","year":"2018","journal-title":"Respir. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"34883","DOI":"10.1074\/jbc.M112.361352","article-title":"Neutrophil elastase modulates cytokine expression: Contribution to host defense against pseudomonas aeruginosa-induced pneumonia","volume":"287","author":"Benabid","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1172\/JCI114699","article-title":"Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch","volume":"86","author":"Tosi","year":"1990","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1136\/thx.2003.014902","article-title":"Linkage of neutrophil serine proteases and decreased surfactant protein-A (SP-A) levels in inflammatory lung disease","volume":"59","author":"Rubio","year":"2004","journal-title":"Thorax"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12931-017-0691-x","article-title":"Neutrophil elastase in bronchiectasis","volume":"18","author":"Gramegna","year":"2017","journal-title":"Respir. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5578","DOI":"10.1073\/pnas.87.14.5578","article-title":"The cysteine switch: A principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family","volume":"87","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/bdrc.20065","article-title":"Matrix metalloproteinases in development and disease","volume":"78","year":"2006","journal-title":"Birth Defects Res. Part C Embryo Today Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1182\/blood.V96.8.2673","article-title":"Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-\u03b1 and leaves RANTES and MCP-2 intact","volume":"96","author":"Proost","year":"2000","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/S0092-8674(00)00087-8","article-title":"The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B\/MMP-9 in vivo","volume":"102","author":"Liu","year":"2000","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1165\/ajrcmb.22.2.3767","article-title":"Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed mainly by mast cells in normal dog airways","volume":"22","author":"Wolters","year":"2000","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/rr29","article-title":"Importance of lysosomal cysteine proteases in lung disease","volume":"1","author":"Wolters","year":"2000","journal-title":"Respir. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1056\/NEJMoa2021713","article-title":"Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis","volume":"383","author":"Chalmers","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0009-8981(67)90181-7","article-title":"The polymorphism of \u201cprealbumins\u201d and \u03b11-antitrypsin in human sera","volume":"16","author":"Fagerhol","year":"1967","journal-title":"Clin. Chim. Acta"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1164\/rccm.201108-1428CI","article-title":"A review of \u03b11-antitrypsin deficiency","volume":"185","author":"Stoller","year":"2012","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2827","DOI":"10.2147\/COPD.S271810","article-title":"The Distribution of Alpha-1 Antitrypsin Genotypes Between Patients with COPD\/Emphysema, Asthma and Bronchiectasis","volume":"15","author":"Veith","year":"2020","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1136\/thoraxjnl-2011-201321","article-title":"Serum levels and genotype distribution of \u03b11-antitrypsin in the general population","volume":"67","author":"Ferrarotti","year":"2012","journal-title":"Thorax"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.rmedc.2011.04.001","article-title":"Alpha-1 antitrypsin deficiency","volume":"4","author":"Kelly","year":"2011","journal-title":"Respir. Med. CME"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/rr18","article-title":"The role of secretory leukocyte proteinase inhibitor and elafin (elastase-specific inhibitor\/skin-derived antileukoprotease) as alarm antiproteinases in inflammatory lung disease","volume":"1","author":"Sallenave","year":"2000","journal-title":"Respir. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1172\/JCI0213572","article-title":"Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic cell clearance in cystic fibrosis and bronchiectasis","volume":"109","author":"Vandivier","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1164\/ajrccm.155.4.9105057","article-title":"Elevated levels of cytokeratin 19 in the bronchoalveolar lavage fluid of patients with chronic airway inflammatory diseases\u2014A specific marker for bronchial epithelial injury","volume":"155","author":"Nakamura","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/0954-6111(93)90072-8","article-title":"Effect of antibiotics on sputum inflammatory contents in acute exacerbations of bronchiectasis","volume":"87","author":"Ip","year":"1993","journal-title":"Respir. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1164\/rccm.201809-1651OC","article-title":"Airway Bacterial Load and Inhaled Antibiotic Response in Bronchiectasis","volume":"200","author":"Sibila","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pupt.2019.101856","article-title":"Evaluation of active neutrophil elastase in sputum of bronchiectasis and cystic fibrosis patients: A comparison among different techniques","volume":"59","author":"Oriano","year":"2019","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_69","first-page":"4718","article-title":"Desmosine is a predictor of long-term cardiovascular mortality in bronchiectasis","volume":"56","author":"Huang","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1111\/resp.12582","article-title":"Sputum matrix metalloproteinase-8 and -9 and tissue inhibitor of metalloproteinase-1 in bronchiectasis: Clinical correlates and prognostic implications","volume":"20","author":"Guan","year":"2015","journal-title":"Respirology"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.rmed.2017.02.001","article-title":"Matrix metalloproteinases and airway remodeling and function in primary ciliary dyskinesia","volume":"124","author":"Pifferi","year":"2017","journal-title":"Respir. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/s41591-021-01289-7","article-title":"Integrative microbiomics in bronchiectasis exacerbations","volume":"27","author":"Narayana","year":"2021","journal-title":"Nat. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S2213-2600(18)30053-5","article-title":"Bronchiectasis: New therapies and new perspectives","volume":"6","author":"Chalmers","year":"2018","journal-title":"Lancet Respir. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1136\/thoraxjnl-2019-214195","article-title":"Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis","volume":"75","author":"Carreto","year":"2020","journal-title":"Thorax"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1378\/chest.117.2.415","article-title":"Distribution of alpha(1)-antitrypsin alleles in patients with bronchiectasis","volume":"117","author":"Cuvelier","year":"2000","journal-title":"Chest"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.rmed.2012.12.009","article-title":"Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis","volume":"107","author":"Stockley","year":"2013","journal-title":"Respir. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.pupt.2019.03.009","article-title":"Safety and efficacy of the human neutrophil elastase inhibitor BAY 85-8501 for the treatment of non-cystic fibrosis bronchiectasis: A randomized controlled trial","volume":"56","author":"Watz","year":"2019","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.jcf.2019.08.020","article-title":"Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis","volume":"19","author":"Barth","year":"2020","journal-title":"J. Cyst. Fibros. Off. J. Eur. Cyst. Fibros. Soc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1111\/bcp.13398","article-title":"Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660)","volume":"83","author":"Miller","year":"2017","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"687","DOI":"10.3109\/15412555.2013.800852","article-title":"Safety and Pharmacokinetics of 120 mg\/kg versus 60 mg\/kg Weekly Intravenous Infusions of Alpha-1 Proteinase Inhibitor in Alpha-1 Antitrypsin Deficiency: A Multicenter, Randomized, Double-Blind, Crossover Study (SPARK)","volume":"10","author":"Campos","year":"2013","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3109\/15412555.2013.804500","article-title":"Biochemical Efficacy and Safety of a New, Ready-to-Use, Liquid Alpha-1-Proteinase Inhibitor, GLASSIA (Alpha1-Proteinase Inhibitor (Human), Intravenous)","volume":"11","author":"Sandhaus","year":"2014","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_82","first-page":"PA999","article-title":"Safety of bi-weekly infusion of A1-PI augmentation therapy in RAPID","volume":"46","author":"Seersholm","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1080\/15412555.2017.1376044","article-title":"Bioequivalence of a Liquid Formulation of Alpha(1)-Proteinase Inhibitor Compared with Prolastin\u00ae-C (Lyophilized Alpha(1)-PI) in Alpha(1)-Antitrypsin Deficiency","volume":"14","author":"Barker","year":"2017","journal-title":"COPD J. Chronic Obstr. Pulm. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"288","DOI":"10.5414\/CP201674","article-title":"Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD","volume":"51","author":"Gunawardena","year":"2013","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_85","first-page":"3416","article-title":"The novel elastase inhibitor BAY 85-8501 provides a new approach in the treatment of pulmonary diseases","volume":"44","author":"Nagelschmitz","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_86","unstructured":"Carnini, C., Brogin, G., Patacchini, R., Miglietta, D., Stefani, M., Finch, H., Fitzgerald, M., Fox, C., Puccini, P., and Villetti, G. (2017). CHF6333: Pharmacological and pharmacokinetic characterization of a novel potent inhaled inhibitor of neutrophil elastase. B80-A: Mechanisms and Models of Acute Lung Injury, American Thoracic Society. American Thoracic Society International Conference Abstracts."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1177\/1753465812438387","article-title":"Reduction of severe exacerbations and hospitalization-derived costs in alpha-1-antitrypsin-deficient patients treated with alpha-1-antitrypsin augmentation therapy","volume":"6","author":"Torres","year":"2012","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_88","first-page":"100","article-title":"Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence","volume":"6","author":"Brantly","year":"2018","journal-title":"Chronic Obstr. Pulm. Dis."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:59Z","timestamp":1760162999000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/11\/5996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":88,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["ijms22115996"],"URL":"https:\/\/doi.org\/10.3390\/ijms22115996","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,1]]}}}