{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T20:48:53Z","timestamp":1792097333281,"version":"4.4.0"},"reference-count":216,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T00:00:00Z","timestamp":1620518400000},"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>Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.<\/jats:p>","DOI":"10.3390\/ijms22095018","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T21:32:46Z","timestamp":1620595966000},"page":"5018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6492-7310","authenticated-orcid":false,"given":"Michael C.","family":"McKelvey","sequence":"first","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Brown","sequence":"additional","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sin\u00e9ad","family":"Ryan","sequence":"additional","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4057-2199","authenticated-orcid":false,"given":"Marcus A.","family":"Mall","sequence":"additional","affiliation":[{"name":"Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), 10178 Berlin, Germany"},{"name":"German Center for Lung Research (DZL), 35392 Gie\u00dfen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5628-6624","authenticated-orcid":false,"given":"Sin\u00e9ad","family":"Weldon","sequence":"additional","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford C.","family":"Taggart","sequence":"additional","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,9]]},"reference":[{"key":"ref_1","first-page":"2210","article-title":"Overview of transcriptomic analysis of all human proteases, non-proteolytic homologs and inhibitors: Organ, tissue and ovarian cancer cell line expression profiling of the human protease degradome by the CLIP-CHIPTM DNA microarray","volume":"1864","author":"Kappelhoff","year":"2017","journal-title":"BBA-Mol. 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