The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo

TY - JOUR

T1 - The fibrinogen cleavage product Aα-Val360, a specific marker of neutrophil elastase activity in vivo

AU - Carter, Richard I

AU - Mumford, Richard A

AU - Treonze, Kelly M

AU - Finke, Paul E

AU - Davies, Phillip

AU - Si, Qian

AU - Humes, John L

AU - Dirksen, Asger

AU - Piitulainen, Eeva

AU - Ahmad, Ali

AU - Stockley, Robert A

PY - 2011/8

Y1 - 2011/8

N2 - 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-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. Trial registration: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

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

U2 - http://dx.doi.org/10.1136/thx.2010.154690

DO - http://dx.doi.org/10.1136/thx.2010.154690

M3 - Journal article

SN - 0040-6376

VL - 66

SP - 686

EP - 691

JO - Thorax

JF - Thorax

IS - 8

ER -