Projects per year
Abstract
compromises mucociliary clearance, favoring mucus plugging and chronic bacterial infection. Inhibitors of ENaC have therapeutic potential in CF airways to reduce the hyperstimulated sodium and fluid absorption to levels which can restore airways hydration.
Objectives: To determine whether a novel compound (QUB-TL1) designed to inhibit protease/ENaC signaling in CF airways restores ASL volume and mucociliary function.
Methods: Protease activity was measured using fluorogenic activity assays. Differentiated primary airway epithelial cell cultures (F508del homozygotes) were used to determined ENaC activity (Ussing chamber recordings), ASL height (confocal microscopy) and mucociliary function (by tracking the surface flow of apically applied microbeads). Cell toxicity was measured by LDH assay.
Measurements and Results: QUB-TL1 inhibits extracellularly-located CAPs, including prostasin, matriptase and furin, the activities of which are observed at excessive levels at the apical surface of CF airway epithelial cells (AECs). QUB-TL1-mediated CAPs inhibition results in diminished ENaC-mediated Na+ absorption in CF AECs due to internalization of a prominent pool of cleaved (active) ENaCγ from the cell surface. Importantly, diminished ENaC activity correlates with improved airway hydration status and mucociliary clearance. We further demonstrate QUB-TL1-mediated furin inhibition, which is in contrast to other serine protease inhibitors (camostat mesylate and aprotinin), affords protection against neutrophil elastase-mediated ENaC activation and Pseudomonas aeruginosa exotoxin A induced cell death.
Conclusions: QUB-TL1 corrects aberrant CAP activities providing a mechanism to delay or prevent the development of CF lung disease in a manner independent of CFTR mutation.
Original language | English |
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Pages (from-to) | 701-710 |
Number of pages | 10 |
Journal | American Journal of Respiratory and Critical Care Medicine |
Volume | 194 |
Issue number | 6 |
Early online date | 25 Mar 2016 |
DOIs | |
Publication status | Published - Sept 2016 |
Keywords
- channel activating proteases
- prostasin
- furin
- pseudomonas aeruginosa exotoxin
ASJC Scopus subject areas
- General Biochemistry,Genetics and Molecular Biology
- General Medicine
Fingerprint
Dive into the research topics of 'Inhibition of Protease–Epithelial Sodium Channel Signaling Improves Mucociliary Function in Cystic Fibrosis Airways'. Together they form a unique fingerprint.-
R2634PMY: Channel activating proteases (CAPS): identification of novel targets for correcting sodium channel dysfunction in CF
Martin, L. (PI), Elborn, S. (CoI) & Walker, B. (CoI)
01/08/2009 → …
Project: Research
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R2887PMY: Channel Activating Proteases (CAPS): molecular targets for correction of sodium channel dysfunction in airways disease
Martin, L. (PI), Elborn, S. (CoI) & Walker, B. (CoI)
01/08/2012 → 31/12/2015
Project: Research
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American Society for Biochemistry and Molecular Biology: Serine proteases in pericellular proteolysis and signaling
Martin, L. (Invited speaker)
02 Nov 2023 → 03 Nov 2023Activity: Talk or presentation types › Invited or keynote talk at national or international conference
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North American Cystic Fibrosis Conference, Orlando, United States. WO5 CLIN: Noteworthy Publication Articles Session.
Martin, L. (Invited speaker)
27 Oct 2016Activity: Talk or presentation types › Invited talk
Press/Media
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Cystic fibrosis: Queen's University Belfast scientists discover molecule that could prolong life of those with the condition
13/05/2016
1 Media contribution
Press/Media: Research
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Scientists develop new treatment to prolong life of those with cystic fibrosis
12/05/2016
1 Media contribution
Press/Media: Research
Profiles
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Putting the CAP on ENaC: The role of serine proteases in the regulation of airways hydration and mucociliary clearance in chronic airways diseases.
Martin, L., 02 Nov 2023.Research output: Contribution to conference › Paper › peer-review
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A novel inhibitor of channel activating proteases: Putting the CAP on ENaC
Reihill, J. A., Walker, B., Harvey, B., Stutts, J., Elborn, J. S. & Martin, S. L., Oct 2015, In: Pediatric Pulmonology. 50, Suppl 41, p. 229 1 p.Research output: Contribution to journal › Meeting abstract › peer-review
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Targeting trypsin-like proteases in cystic fibrosis airways
Reihill, J., Walker, B., Elborn, J. & Martin, L., 23 Oct 2014.Research output: Contribution to conference › Paper › peer-review