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 Aα-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.
Aα-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 Aα-Val360, but was approximately 17 times higher than for the elastase footprint, consistent with a greater potential contribution to lung damage. Aα-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., Bolton, C. E., Hopkinson, N. S., Mahadeva, R., Steiner, M. C., Wilkinson, T. M., Sapey, E., & 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
• Contract Date: Jun 20, 2019