Paul R. Newby
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.
Authors
Diana Crossley
Helena Crisford
James A. Stockley
Richard A. Mumford
Richard I. Carter
Professor CHARLOTTE BOLTON charlotte.bolton@nottingham.ac.uk
Professor of Respiratory Medicine
Nicholas S. Hopkinson
Ravi Mahadeva
Michael C. Steiner
Tom M.A. Wilkinson
Elizabeth Sapey
Robert A. Stockley
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
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 |
Files
ERJ Open Paper
(857 Kb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by-nc/4.0/
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