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The fibrinogen cleavage product A alpha-Val(360), a specific marker of neutrophil elastase activity in vivo

Carter, Richard I.; Mumford, Richard A.; Treonze, Kelly M.; Finke, Paul E.; Davies, Phillip; Si, Qian; Humes, John L.; Dirksen, Asger; Piitulainen, Eeva LU and Ahmad, Ali, et al. (2011) In Thorax 66(8). p.686-691
Abstract
Background Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s. Methods In pilot studies, plasma A alpha-Val(360) and markers of... (More)
Background Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s. Methods In pilot studies, plasma A alpha-Val(360) and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. A alpha-Val(360) and sputum elastase activity were also measured in a further seven PiZ A1AT-deficient subjects over the course of an acute exacerbation. Finally, A alpha-Val(360) was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial. Results The plasma concentrations of A alpha-Val(360) and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of A alpha-Val(360) and subsequent A1AT/NE complex formation. A alpha-Val(360) was related to the spirometric severity of lung disease in A1AT deficiency, to sputum elastase activity in acute exacerbations and was decreased in subjects receiving A1AT replacement therapy (while remaining constant in those receiving placebo). Conclusions A alpha-Val(360) represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD. (Less)
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Contribution to journal
publication status
published
subject
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Thorax
volume
66
issue
8
pages
686 - 691
publisher
BMJ Publishing Group
external identifiers
  • wos:000292916400011
  • scopus:79960617712
ISSN
1468-3296
DOI
10.1136/thx.2010.154690
language
English
LU publication?
yes
id
bbbbd5be-3c02-4fd1-98d0-333d68370b51 (old id 2072547)
date added to LUP
2011-09-02 08:32:41
date last changed
2017-11-12 03:48:24
@article{bbbbd5be-3c02-4fd1-98d0-333d68370b51,
  abstract     = {Background Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s. Methods In pilot studies, plasma A alpha-Val(360) and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. A alpha-Val(360) and sputum elastase activity were also measured in a further seven PiZ A1AT-deficient subjects over the course of an acute exacerbation. Finally, A alpha-Val(360) was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial. Results The plasma concentrations of A alpha-Val(360) and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of A alpha-Val(360) and subsequent A1AT/NE complex formation. A alpha-Val(360) was related to the spirometric severity of lung disease in A1AT deficiency, to sputum elastase activity in acute exacerbations and was decreased in subjects receiving A1AT replacement therapy (while remaining constant in those receiving placebo). Conclusions A alpha-Val(360) represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD.},
  author       = {Carter, Richard I. and Mumford, Richard A. and Treonze, Kelly M. and Finke, Paul E. and Davies, Phillip and Si, Qian and Humes, John L. and Dirksen, Asger and Piitulainen, Eeva and Ahmad, Ali and Stockley, Robert A.},
  issn         = {1468-3296},
  language     = {eng},
  number       = {8},
  pages        = {686--691},
  publisher    = {BMJ Publishing Group},
  series       = {Thorax},
  title        = {The fibrinogen cleavage product A alpha-Val(360), a specific marker of neutrophil elastase activity in vivo},
  url          = {http://dx.doi.org/10.1136/thx.2010.154690},
  volume       = {66},
  year         = {2011},
}