A Specific Proteinase 3 Activity Footprint in Alpha-1-antitrypsin Deficiency

Newby, Paul R.; Crossley, Diana; Crisford, Helena; Stockley, James A.; Mumford, Richard A.; Carter, Richard I.; Bolton, Charlotte E.; Hopkinson, Nicholas S.; Mahadeva, Ravi; Steiner, Michael C.; Wilkinson, Tom M.A.; Sapey, Elizabeth; Stockley, Robert A.

Abstract

Alpha-1-antitrypsin deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase has long been considered the enzyme responsible. However, proteinase 3 also produces the pathological features of Chronic Obstructive Pulmonary Disease, is present in the same granules in the neutrophil and is inhibited after neutrophil elastase. We developed a specific footprint assay for proteinase 3 activity and assessed its relationship to a neutrophil elastase footprint in Alpha-1-antitrypsin deficiency.
An ELISA was developed for the specific proteinase 3 fibrinogen cleavage site A?-Val541. Levels were measured in plasma from 239 PiZZ, 94 PiSZ patients, 53 non-deficient healthy smokers and 78 individuals with usual Chronic Obstructive Pulmonary Disease. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomographic scanning.
A?-Val541 was greater than the elastase footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ antitrypsin deficient patients and correlated with the elastase marker A?-Val360, but was approximately 17 times higher than for the elastase footprint, consistent with a greater potential contribution to lung damage. A?-Val541 was related cross-sectionally to the severity of lung disease (FEV1 % predicted; r=-0.284; p

Citation

Newby, P. R., Crossley, D., Crisford, H., Stockley, J. A., Mumford, R. A., Carter, R. I., …Stockley, R. A. (2019). A Specific Proteinase 3 Activity Footprint in Alpha-1-antitrypsin Deficiency. ERJ Open Research, 5(3), Article 00095-2019. https://doi.org/10.1183/23120541.00095-2019

• Journal Article Type: Article
• Acceptance Date: Jun 18, 2019
• Online Publication Date: Aug 5, 2019
• Publication Date: Jul 1, 2019
• Deposit Date: Jun 20, 2019
• Publicly Available Date: Jun 20, 2019
• Journal: ERJ Open Research
• Electronic ISSN: 2312-0541
• Publisher: European Respiratory Society
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 3
• Article Number: 00095-2019
• DOI: https://doi.org/10.1183/23120541.00095-2019
• Public URL: https://nottingham-repository.worktribe.com/output/2211381
• Publisher URL: https://openres.ersjournals.com/content/5/3/00095-2019