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Am J Respir Crit Care Med. 2019 Oct 18. doi: 10.1164/rccm.201906-1190PP. [Epub ahead of print]

Targeting Proteases in Cystic Fibrosis Lung Disease: Paradigms, Progress, and Potential.

Author information

1
Queen's University of Belfast, Airway Innate Immunity Group, Wellcome Wolfson Institute for Experimental Medicine, Belfast, United Kingdom of Great Britain and Northern Ireland.
2
Queen's University Belfast, Airway Innate Immunity Group, Wellcome Wolfson Institute for Experimental Medicine, Belfast, United Kingdom of Great Britain and Northern Ireland.
3
University of Belfast, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Belfast, United Kingdom of Great Britain and Northern Ireland.
4
Charité Universitätsmedizin Berlin, Berlin, Germany.
5
Queen's University of Belfast, Airway Innate Immunity Group, Wellcome Wolfson Institute for Experimental Medicine, Belfast, United Kingdom of Great Britain and Northern Ireland; c.taggart@qub.ac.uk.

Abstract

Cystic fibrosis (CF) is the most common life-limiting hereditary condition of Caucasian populations and is characterised by chronic airways inflammation driving progressive structural lung damage. Despite tremendous advances in the treatment of CF and concomitant increased life expectancy for patients, chronic lung disease remains the main cause of morbidity and mortality among CF patients. While universal restoration of cystic fibrosis transmembrane conductance regulator activity remains a future hope, novel therapies aimed at reducing or preventing chronic airways inflammation and progressive structural lung damage are required. It is well-established that proteolytic enzymes are important in the CF lung beyond the basic turnover of proteins and intracellular degradation of pathogens. When secreted, these enzymes play key roles in extracellular substrate modification implicated in important biological processes such as matrix and airway remodelling, goblet cell metaplasia and mucus hypersecretion, immune cell recruitment and dysregulation of epithelial ion channels. Importantly, the burden of proteases in the CF lung is significantly elevated, overwhelming the endogenous antiprotease shield. Indeed, free protease activity has emerged as a major risk factor of the onset and progression of bronchiectasis and lung function decline in patients with CF. Recent research has highlighted the importance of new players such as cathepsin S and matrix metalloprotease-12, as well as the membrane-associated activity of key proteases such as neutrophil elastase on the surface of neutrophils. Here, we review the current knowledge and emerging concepts of the role of host proteases in the pathogenesis of CF lung disease and their potential as therapeutic targets.

KEYWORDS:

Inflammation; Protease; Protease inhibitor

PMID:
31626562
DOI:
10.1164/rccm.201906-1190PP

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