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The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases
The serine proteases released by activated polymorphonuclear neutrophils [NSPs (neutrophil serine proteases)] contribute to a variety of inflammatory lung diseases, including CF (cystic fibrosis). They are therefore key targets for the development of efficient inhibitors. Although rodent models have...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492928/ https://www.ncbi.nlm.nih.gov/pubmed/22860995 http://dx.doi.org/10.1042/BJ20120818 |
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author | Bréa, Déborah Meurens, François Dubois, Alice V. Gaillard, Julien Chevaleyre, Claire Jourdan, Marie-Lise Winter, Nathalie Arbeille, Brigitte Si-Tahar, Mustapha Gauthier, Francis Attucci, Sylvie |
author_facet | Bréa, Déborah Meurens, François Dubois, Alice V. Gaillard, Julien Chevaleyre, Claire Jourdan, Marie-Lise Winter, Nathalie Arbeille, Brigitte Si-Tahar, Mustapha Gauthier, Francis Attucci, Sylvie |
author_sort | Bréa, Déborah |
collection | PubMed |
description | The serine proteases released by activated polymorphonuclear neutrophils [NSPs (neutrophil serine proteases)] contribute to a variety of inflammatory lung diseases, including CF (cystic fibrosis). They are therefore key targets for the development of efficient inhibitors. Although rodent models have contributed to our understanding of several diseases, we have previously shown that they are not appropriate for testing anti-NSP therapeutic strategies [Kalupov, Brillard-Bourdet, Dade, Serrano, Wartelle, Guyot, Juliano, Moreau, Belaaouaj and Gauthier (2009) J. Biol. Chem. 284, 34084–34091). Thus NSPs must be characterized in an animal model that is much more likely to predict how therapies will act in humans in order to develop protease inhibitors as drugs. The recently developed CFTR(−/−) (CFTR is CF transmembrane conductance regulator) pig model is a promising alternative to the mouse model of CF [Rogers, Stoltz, Meyerholz, Ostedgaard, Rokhlina, Taft, Rogan, Pezzulo, Karp, Itani et al. (2008) Science 321, 1837–1841]. We have isolated blood neutrophils from healthy pigs and determined their responses to the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus, and the biochemical properties of their NSPs. We used confocal microscopy and antibodies directed against their human homologues to show that the three NSPs (elastase, protease 3 and cathepsin G) are enzymatically active and present on the surface of triggered neutrophils and NETs (neutrophil extracellular traps). All of the porcine NSPs are effectively inhibited by human NSP inhibitors. We conclude that there is a close functional resemblance between porcine and human NSPs. The pig is therefore a suitable animal model for testing new NSP inhibitors as anti-inflammatory agents in neutrophil-associated diseases such as CF. |
format | Online Article Text |
id | pubmed-3492928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-34929282012-11-08 The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases Bréa, Déborah Meurens, François Dubois, Alice V. Gaillard, Julien Chevaleyre, Claire Jourdan, Marie-Lise Winter, Nathalie Arbeille, Brigitte Si-Tahar, Mustapha Gauthier, Francis Attucci, Sylvie Biochem J Research Article The serine proteases released by activated polymorphonuclear neutrophils [NSPs (neutrophil serine proteases)] contribute to a variety of inflammatory lung diseases, including CF (cystic fibrosis). They are therefore key targets for the development of efficient inhibitors. Although rodent models have contributed to our understanding of several diseases, we have previously shown that they are not appropriate for testing anti-NSP therapeutic strategies [Kalupov, Brillard-Bourdet, Dade, Serrano, Wartelle, Guyot, Juliano, Moreau, Belaaouaj and Gauthier (2009) J. Biol. Chem. 284, 34084–34091). Thus NSPs must be characterized in an animal model that is much more likely to predict how therapies will act in humans in order to develop protease inhibitors as drugs. The recently developed CFTR(−/−) (CFTR is CF transmembrane conductance regulator) pig model is a promising alternative to the mouse model of CF [Rogers, Stoltz, Meyerholz, Ostedgaard, Rokhlina, Taft, Rogan, Pezzulo, Karp, Itani et al. (2008) Science 321, 1837–1841]. We have isolated blood neutrophils from healthy pigs and determined their responses to the bacterial pathogens Pseudomonas aeruginosa and Staphylococcus aureus, and the biochemical properties of their NSPs. We used confocal microscopy and antibodies directed against their human homologues to show that the three NSPs (elastase, protease 3 and cathepsin G) are enzymatically active and present on the surface of triggered neutrophils and NETs (neutrophil extracellular traps). All of the porcine NSPs are effectively inhibited by human NSP inhibitors. We conclude that there is a close functional resemblance between porcine and human NSPs. The pig is therefore a suitable animal model for testing new NSP inhibitors as anti-inflammatory agents in neutrophil-associated diseases such as CF. Portland Press Ltd. 2012-10-05 2012-11-01 /pmc/articles/PMC3492928/ /pubmed/22860995 http://dx.doi.org/10.1042/BJ20120818 Text en © 2012 The Author(s) The author(s) has paid for this article to be freely available under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by-nc/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Bréa, Déborah Meurens, François Dubois, Alice V. Gaillard, Julien Chevaleyre, Claire Jourdan, Marie-Lise Winter, Nathalie Arbeille, Brigitte Si-Tahar, Mustapha Gauthier, Francis Attucci, Sylvie The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title_full | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title_fullStr | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title_full_unstemmed | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title_short | The pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
title_sort | pig as a model for investigating the role of neutrophil serine proteases in human inflammatory lung diseases |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492928/ https://www.ncbi.nlm.nih.gov/pubmed/22860995 http://dx.doi.org/10.1042/BJ20120818 |
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