A specific proteinase 3 activity footprint in α 1 -antitrypsin deficiency.

التفاصيل البيبلوغرافية
العنوان:	A specific proteinase 3 activity footprint in α 1 -antitrypsin deficiency.
المؤلفون:	Newby PR; Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital Birmingham, Birmingham, UK., Crossley D; Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital Birmingham, Birmingham, UK., Crisford H; Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital Birmingham, Birmingham, UK., Stockley JA; University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK., Mumford RA; Mumford Pharma, Red Bank, NJ, USA., Carter RI; Dept of Respiratory Medicine, New Cross Hospital, Wolverhampton, UK., Bolton CE; Nottingham Respiratory Research Unit, Nottingham NIHR Biomedical Research Centre, University of Nottingham, Nottingham, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration., Hopkinson NS; Respiratory NIHR Biomedical Research Centre, Royal Brompton and Harefield NHS Foundation Trust, London, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration., Mahadeva R; Dept of Medicine, Cambridge NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration., Steiner MC; Institute for Lung Health, NIHR Leicester Biomedical Research Centre - Respiratory, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration., Wilkinson TMA; Respiratory NIHR Biomedical Research Centre, University of Southampton, Southampton, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration., Sapey E; Institute of Inflammation and Ageing, University of Birmingham, Queen Elizabeth Hospital Birmingham, Birmingham, UK., Stockley RA; University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham, Birmingham, UK.; Members of the NIHR Rare Diseases Translational Research Collaboration.
المصدر:	ERJ open research [ERJ Open Res] 2019 Aug 05; Vol. 5 (3). Date of Electronic Publication: 2019 Aug 05 (Print Publication: 2019).
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: European Respiratory Society Country of Publication: England NLM ID: 101671641 Publication Model: eCollection Cited Medium: Print ISSN: 2312-0541 (Print) Linking ISSN: 23120541 NLM ISO Abbreviation: ERJ Open Res Subsets: PubMed not MEDLINE
أسماء مطبوعة:	Original Publication: Sheffield : European Respiratory Society, [2015]-
مستخلص:	α 1 -Antitrypsin (α 1 -AT) deficiency is a risk factor for emphysema due to tissue damage by serine proteases. Neutrophil elastase (NE) has long been considered the enzyme responsible. However, proteinase 3 (PR3) also produces the pathological features of chronic obstructive pulmonary disease (COPD), is present in the same granules in the neutrophil and is inhibited after NE. We developed a specific footprint assay for PR3 activity and assessed its relationship to an NE footprint in α 1 -AT deficiency. An ELISA was developed for the specific PR3 fibrinogen cleavage site Aα-Val ⁵⁴¹ . Levels were measured in plasma from 239 PiZZ patients, 94 PiSZ patients, 53 nondeficient healthy smokers and 78 individuals with usual COPD. Subjects underwent extensive demographic characterisation including full lung function and lung computed tomography scanning. Aα-Val ⁵⁴¹ was greater than the NE footprint in all cohorts, consistent with differential activity. Values were highest in the PiZZ α 1 -AT-deficient patients and correlated with the NE marker Aα-Val ³⁶⁰ , but were ∼17 times higher than for the NE footprint, consistent with a greater potential contribution to lung damage. Aα-Val ⁵⁴¹ was related cross-sectionally to the severity of lung disease (forced expiratory volume in 1 s % pred: r s = -0.284; p<0.001) and was sensitive to augmentation therapy, falling from 287.2 to 48.6 nM (p<0.001). An in vivo plasma footprint of PR3 activity is present in greater quantities than an NE footprint in patients with α 1 -AT deficiency, is sensitive to augmentation therapy and represents a likely biomarker for dose-ranging studies. Competing Interests: Conflict of interest: P.R. Newby reports grants from the West Midlands Chest Fund and the NIHR during the conduct of the study. Conflict of interest: D. Crossley has nothing to disclose. Conflict of interest: H. Crisford has nothing to disclose. Conflict of interest: J.A. Stockley has nothing to disclose. Conflict of interest: R.A. Mumford has nothing to disclose. Conflict of interest: R.I. Carter reports grants from Grifols Talecris during the conduct of the study. Conflict of interest: C.E. Bolton reports grants from Pfizer, GSK, Innovate UK and MRC/ABPI, an honorarium for a presentation (nonpromotional) from Chiesi, and a consultancy fee regarding a research pipeline (nonpromotional) from Boehringer, outside the submitted work. Conflict of interest: N.S. Hopkinson has nothing to disclose. Conflict of interest: R. Mahadeva has received speaker fees for educational talks on COPD from Pfizer, Chiesi and AstraZeneca, and advisory boards for Boehringer Ingelheim and Kamada, and has grant support from Pfizer Open Air for an unrelated research study. Conflict of interest: M.C. Steiner reports advisory board fees, nonfinancial support for travel to international conferences and speaker honoraria from Boehringer Ingelheim and GSK, and advisory board fees from Nutricia, outside the submitted work. Conflict of interest: T.M.A. Wilkinson has nothing to disclose. Conflict of interest: E. Sapey reports grants from the Medical Research Council, the Wellcome Trust, the Alpha 1 Foundation and the NIHR, outside the submitted work. Conflict of interest: R.A. Stockley reports personal fees from AstraZeneca, Medimmune, Almirall, Nycomed, Takeda, Boehringer Ingelheim, CSL Behring, Kamada, Baxter, Chiesi and Polyphor, outside the submitted work.
References:	Am J Respir Cell Mol Biol. 1999 Apr;20(4):729-36. (PMID: 10101005) J Immunol. 2000 Sep 15;165(6):3366-74. (PMID: 10975855) Am J Respir Crit Care Med. 2001 Mar;163(3 Pt 1):737-44. (PMID: 11254533) Physiol Rev. 2003 Apr;83(2):309-36. (PMID: 12663861) Acta Med Scand. 1964 Feb;175:197-205. (PMID: 14124635) Eur Respir J. 2004 May;23(5):769-75. (PMID: 15176695) Eur Respir J. 2009 Jun;33(6):1345-53. (PMID: 19196813) COPD. 2009 Jun;6(3):177-84. (PMID: 19811373) Thorax. 2011 Aug;66(8):686-91. (PMID: 21617168) Eur Respir J. 2013 Jan;41(1):31-8. (PMID: 22523359) Eur Respir J. 2012 Dec;40(6):1324-43. (PMID: 22743675) Eur Respir J. 2013 May;41(5):1042-50. (PMID: 22936713) Int J Chron Obstruct Pulmon Dis. 2014 Feb 07;9:163-77. (PMID: 24532968) Ann Am Thorac Soc. 2014 Jul;11(6):859-64. (PMID: 24950156) Am J Physiol Lung Cell Mol Physiol. 2015 Jan 15;308(2):L179-90. (PMID: 25416382) Chest. 2015 Aug;148(2):382-388. (PMID: 25569856) Lancet. 2015 Jul 25;386(9991):360-8. (PMID: 26026936) Eur Respir J. 2017 Mar 6;49(3):. (PMID: 28182564) Sci Rep. 2019 Mar 11;9(1):4064. (PMID: 30858579) J Clin Invest. 1988 Dec;82(6):1963-73. (PMID: 3198760) Am Rev Respir Dis. 1985 Aug;132(2):362-6. (PMID: 3849280) J Appl Physiol Respir Environ Exerc Physiol. 1979 Dec;47(6):1315-24. (PMID: 536303) J Immunol. 1996 Sep 15;157(6):2624-31. (PMID: 8805666)
معلومات مُعتمدة:	MR/L008335/1 United Kingdom MRC_ Medical Research Council
تواريخ الأحداث:	Date Created: 20190813 Latest Revision: 20210110
رمز التحديث:	20240628
مُعرف محوري في PubMed:	PMC6680069
DOI:	10.1183/23120541.00095-2019
PMID:	31403052
قاعدة البيانات:	MEDLINE

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تدمد:	2312-0541
DOI:	10.1183/23120541.00095-2019