RT Journal Article SR Electronic T1 The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo JF Thorax JO Thorax FD BMJ Publishing Group Ltd and British Thoracic Society SP 686 OP 691 DO 10.1136/thx.2010.154690 VO 66 IS 8 A1 Richard I Carter A1 Richard A Mumford A1 Kelly M Treonze A1 Paul E Finke A1 Phillip Davies A1 Qian Si A1 John L Humes A1 Asger Dirksen A1 Eeva Piitulainen A1 Ali Ahmad A1 Robert A Stockley YR 2011 UL http://thorax.bmj.com/content/66/8/686.abstract AB 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.