title: The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo.
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-Val(360) and markers of neutrophil activation were measured in 95 subjects with a range of A1AT concentrations. Aα-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, Aα-Val(360) was measured in plasma from subjects randomised to receive A1AT replacement or placebo in the EXACTLE trial.
  
  
  RESULTS
  The plasma concentrations of Aα-Val(360) and A1AT related exponentially, consistent with previous theoretical and in vitro experimental data. L-233 (an intracellular NE inhibitor) blocked generation of Aα-Val(360) and subsequent A1AT/NE complex formation. Aα-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
  Aα-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.
  
  
  BACKGROUND
  The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.
authors: Lung Function and Sleep Department, ADAPT Office (Office 4), Queen Elizabeth Hospital, Birmingham B15 2WB, UK.
authors: Richard I
authors: RI
authors: Carter
authors: Richard A
authors: RA
authors: Mumford
authors: Kelly M
authors: KM
authors: Treonze
authors: Paul E
authors: PE
authors: Finke
authors: Phillip
authors: P
authors: Davies
authors: Qian
authors: Q
authors: Si
authors: John L
authors: JL
authors: Humes
authors: Asger
authors: A
authors: Dirksen
authors: Eeva
authors: E
authors: Piitulainen
authors: Ali
authors: A
authors: Ahmad
authors: Robert A
authors: RA
authors: Stockley