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Original article
The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo
  1. Richard I Carter1,
  2. Richard A Mumford2,3,
  3. Kelly M Treonze2,
  4. Paul E Finke2,
  5. Phillip Davies2,
  6. Qian Si2,
  7. John L Humes2,
  8. Asger Dirksen4,
  9. Eeva Piitulainen5,
  10. Ali Ahmad6,
  11. Robert A Stockley1
  1. 1Lung Function and Sleep Department, The ADAPT Project, Queen Elizabeth Hospital, Birmingham, UK
  2. 2Merck Research Laboratories, Rahway, New Jersey, USA
  3. 3Mumford Pharma Consulting, New Jersey, USA
  4. 4Gentofte University Hospital, Hellerup, Denmark
  5. 5University Hospital, Malmö, Sweden
  6. 6University of Birmingham, Birmingham, UK
  1. Correspondence to Professor Robert A Stockley, Lung Function and Sleep Department, ADAPT Office (Office 4), Queen Elizabeth Hospital, Birmingham B15 2WB, UK; rob.stockley{at}uhb.nhs.uk

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 Aα-Val360 and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. Aα-Val360 and sputum elastase activity were also measured in a further seven PiZ A1AT-deficient subjects over the course of an acute exacerbation. Finally, Aα-Val360 was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial.

Results The plasma concentrations of Aα-Val360 and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of Aα-Val360 and subsequent A1AT/NE complex formation. Aα-Val360 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 Aα-Val360 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.

Trial registration The EXACTLE study was registered in ClinicalTrials.gov as ‘Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients’; ClinicalTrials.gov Identifier: NCT00263887.

  • Alpha 1-antitrypsin
  • pulmonary disease
  • chronic obstructive
  • leukocyte elastase
  • biological markers
  • alpha1 antitrypsin deficiency
  • COPD mechanisms
  • COPD exacerbations
  • emphysema
  • neutrophil biology
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Footnotes

  • Funding Talecris Biotherapeutics provided an unrestricted grant to the ADAPT (Antitrypsin Deficiency Assessment and Programme for Treatment) project to support this and ongoing research into alpha-1-antitrypsin deficiency.

  • Competing interests A patent covering L-233 (WO/2009/045419) is held by Merck, Rahway, NJ, USA. PEF and RAM are named inventors on this patent. A patent covering Aα-Val360 (US patent No 6124107) is held by Merck, Rahway, NJ, USA. PD, JLH and RAM are named inventors on this patent. Talecris Biotherapeutics has provided unrestricted grants to the ADAPT project for ongoing research into alpha-1-antitrypsin deficiency and sponsored the EXACTLE trial but had no involvement in the production of this manuscript.

  • Ethics approval Ethical approval for studies relating to patients on the ADAPT (Antitrypsin Assessment and Programme for Treatment) Registry was provided by the University Hospitals Birmingham NHS Trust research ethics committee. The EXACTLE trial was a double blind randomised controlled trial of alpha-1-antitrypsin replacement therapy versus placebo in patients with PiZ alpha-1-antitrypsin deficiency. All patients gave informed consent and the study was approved by the ethics committee of the Capital Region of Denmark (Hillerød, Denmark), the National Health Service West Midlands South Birmingham research ethics committee (Birmingham, UK) and the regional ethics committee of Lund (Lund, Sweden).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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