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Eur Respir J. 2018 Mar 29;51(3). pii: 1701910. doi: 10.1183/13993003.01910-2017. Print 2018 Mar.

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis.

Dittrich AS1,2,3,4, Kühbandner I1,2,3, Gehrig S1,2,4,5, Rickert-Zacharias V1,2,4,5, Twigg M6, Wege S2,3, Taggart CC6, Herth F2,3, Schultz C2,4,5, Mall MA7,2,4,8,9.

Author information

1
Dept of Translational Pulmonology and Division of Paediatric Pulmonology and Allergy and Cystic Fibrosis Centre, University of Heidelberg, Heidelberg, Germany.
2
Translational Lung Research Centre Heidelberg (TLRC), German Centre for Lung Research (DZL), Heidelberg, Germany.
3
Dept of Pneumology and Critical Care Medicine, Thoraxklinik at the University Hospital Heidelberg, Heidelberg, Germany.
4
Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany.
5
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
6
Airway Innate Immunity Group (AiIR), Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
7
Dept of Translational Pulmonology and Division of Paediatric Pulmonology and Allergy and Cystic Fibrosis Centre, University of Heidelberg, Heidelberg, Germany Marcus.mall@charite.de.
8
Dept of Paediatric Pulmonology and Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
9
Berlin Institute of Health (BIH), Berlin, Germany.

Abstract

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1 s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

Conflict of interest statement

Conflict of interest: A.S. Dittrich reports grants from the German Cystic Fibrosis Association Mukoviszidose e.V. (number 1605) and the Heidelberg Research Centre for Molecular Medicine Career Development Fellowship, during the conduct of the study. Conflict of interest: F. Herth has received grants, personal fees and non-financial support from Novartis, Chiesi, Boehringer, Astra, Uptake, Broncus, Pulmonx, Olympus, BTG and Ethicon, outside the submitted work. Conflict of interest: C. Schultz co-founded SiChem in 2001 and still own part of the company. SiChem is the sole producer of FRET probes used in this manuscript. Conflict of interest: M.A. Mall received grants from the German Federal Ministry of Education and Research (grant contract number 82DZL00401 and 82DZL004A1) and the European Commission (Seventh Framework Programme Project number 603038 CFMatters), during the conduct of the study; and personal fees for advisory board participation, consultancy, and lecture fees from Vertex, personal fees for advisory board participation and consultancy, from Spyrex, Polyphor and Boehringer Ingelheim, personal fees for advisory board participation from ProQR, PTC Pharmaceuticals, Arrowhead and Pro Axis, and lecture fees from Bayer, outside the submitted work. In addition, M.A. Mall has a patent on the Scnn1b-transgenic mouse with royalties paid, and a patent on use of sodium channel blockers for early therapy of obstructive lung diseases issued.

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