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A specific proteinase 3 activity footprint in α1-antitrypsin deficiency

A specific proteinase 3 activity footprint in α1-antitrypsin deficiency
A specific proteinase 3 activity footprint in α1-antitrypsin deficiency
α1-Antitrypsin (α1-AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. We developed a specific footprint assay for PR3 activity and assessed its relationship to an NE footprint in α1-AT deficiency.

An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val541. Levels were measured in plasma from 239 PiZZ patients, 94 PiSZ patients, 53 nondeficient healthy smokers and 78 individuals with usual COPD. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomography scanning.

Aα-Val541 was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α1-AT-deficient patients and correlated with the NE marker Aα-Val360, but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val541 was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: rs= −0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001).

An in vivo plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α1-AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies.
2312-0541
1-12
Newby, Paul R.
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Crossley, Diana
e2505c71-26f3-4089-9ac0-01c61da3bbc6
Crisford, Helena
433f088c-9749-4cbf-82bd-007bccbb02b7
Stockley, James A.
df8e9b9a-fe0b-4eb1-bb75-5dc9775c580e
Mumford, Richard A.
c848b79b-6a92-4457-820b-cca35111a812
Carter, Richard I.
95f3d493-a167-47c8-9cb8-eea705d3e68a
Bolton, Charlotte E.
37ee7b93-c989-4b45-9c4e-a3dabbde7ebb
Hopkinson, Nicholas S.
91e9a2af-8ab3-4671-b766-761e82bd5310
Mahadeva, Ravi
40ef2d46-d603-428b-ba4b-783d425ec1ae
Steiner, Michael C.
ecb02779-579c-48df-911d-cb0d992a2a85
Wilkinson, Thomas
8c55ebbb-e547-445c-95a1-c8bed02dd652
Sapey, Elizabeth
7e4891fd-1941-4b33-9cc6-e2c2acaa20c9
Stockley, Robert A.
6a1dc39d-312c-4641-9fb9-be00f3f9e960
Newby, Paul R.
303c90a0-2397-4439-8713-aa093b23e15b
Crossley, Diana
e2505c71-26f3-4089-9ac0-01c61da3bbc6
Crisford, Helena
433f088c-9749-4cbf-82bd-007bccbb02b7
Stockley, James A.
df8e9b9a-fe0b-4eb1-bb75-5dc9775c580e
Mumford, Richard A.
c848b79b-6a92-4457-820b-cca35111a812
Carter, Richard I.
95f3d493-a167-47c8-9cb8-eea705d3e68a
Bolton, Charlotte E.
37ee7b93-c989-4b45-9c4e-a3dabbde7ebb
Hopkinson, Nicholas S.
91e9a2af-8ab3-4671-b766-761e82bd5310
Mahadeva, Ravi
40ef2d46-d603-428b-ba4b-783d425ec1ae
Steiner, Michael C.
ecb02779-579c-48df-911d-cb0d992a2a85
Wilkinson, Thomas
8c55ebbb-e547-445c-95a1-c8bed02dd652
Sapey, Elizabeth
7e4891fd-1941-4b33-9cc6-e2c2acaa20c9
Stockley, Robert A.
6a1dc39d-312c-4641-9fb9-be00f3f9e960

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, Thomas, Sapey, Elizabeth and Stockley, Robert A. (2019) A specific proteinase 3 activity footprint in α1-antitrypsin deficiency. ERJ Open Research, 5 (3), 1-12, [00095-2019]. (doi:10.1183/23120541.00095-2019).

Record type: Article

Abstract

α1-Antitrypsin (α1-AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. We developed a specific footprint assay for PR3 activity and assessed its relationship to an NE footprint in α1-AT deficiency.

An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val541. Levels were measured in plasma from 239 PiZZ patients, 94 PiSZ patients, 53 nondeficient healthy smokers and 78 individuals with usual COPD. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomography scanning.

Aα-Val541 was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α1-AT-deficient patients and correlated with the NE marker Aα-Val360, but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val541 was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: rs= −0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001).

An in vivo plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α1-AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies.

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More information

Accepted/In Press date: 30 June 2019
e-pub ahead of print date: July 2019
Published date: 5 August 2019

Identifiers

Local EPrints ID: 435647
URI: http://eprints.soton.ac.uk/id/eprint/435647
ISSN: 2312-0541
PURE UUID: 453267af-dc10-46a1-973f-fe371985a346

Catalogue record

Date deposited: 15 Nov 2019 17:30
Last modified: 09 Nov 2021 15:45

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Contributors

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

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