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

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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.

Details

Authors
  • Richard I. Carter
  • Richard A. Mumford
  • Kelly M. Treonze
  • Paul E. Finke
  • Phillip Davies
  • Qian Si
  • John L. Humes
  • Asger Dirksen
  • Eeva Piitulainen
  • Ali Ahmad
  • Robert A. Stockley
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Respiratory Medicine and Allergy
Original languageEnglish
Pages (from-to)686-691
JournalThorax
Volume66
Issue number8
Publication statusPublished - 2011
Publication categoryResearch
Peer-reviewedYes