Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.

<h4>Background</h4>Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation...

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Autores principales:	Ross Vlahos, Peter A B Wark, Gary P Anderson, Steven Bozinovski
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/fa6ada3c0271488baac4d36c250aaa40
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spelling	oai:doaj.org-article:fa6ada3c0271488baac4d36c250aaa402021-11-18T07:25:47ZGlucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.1932-620310.1371/journal.pone.0033277https://doaj.org/article/fa6ada3c0271488baac4d36c250aaa402012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22413009/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD.<h4>Methods</h4>Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated.<h4>Results</h4>Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation.<h4>Conclusions</h4>As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.Ross VlahosPeter A B WarkGary P AndersonSteven BozinovskiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e33277 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ross Vlahos Peter A B Wark Gary P Anderson Steven Bozinovski Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
description	<h4>Background</h4>Chronic Obstructive Pulmonary Disease (COPD) is currently the fifth leading cause of death worldwide. Neutrophilic inflammation is prominent, worsened during infective exacerbations and is refractory to glucocorticosteroids (GCs). Deregulated neutrophilic inflammation can cause excessive matrix degradation through proteinase release. Gelatinase and azurophilic granules within neutrophils are a major source of matrix metalloproteinase (MMP)-9 and neutrophil elastase (NE), respectively, which are elevated in COPD.<h4>Methods</h4>Secreted MMP-9 and NE activity in BALF were stratified according to GOLD severity stages. The regulation of secreted NE and MMP-9 in isolated blood neutrophils was investigated using a pharmacological approach. In vivo release of MMP-9 and NE in mice exposed to cigarette smoke (CS) and/or the TLR agonist lipopolysaccharide (LPS) in the presence of dexamethasone (Dex) was investigated.<h4>Results</h4>Neutrophil activation as assessed by NE release was increased in severe COPD (36-fold, GOLD II vs. IV). MMP-9 levels (8-fold) and activity (21-fold) were also elevated in severe COPD, and this activity was strongly associated with BALF neutrophils (r = 0.92, p<0.001), but not macrophages (r = 0.48, p = 0.13). In vitro, release of NE and MMP-9 from fMLP stimulated blood neutrophils was insensitive to Dex and attenuated by the PI3K inhibitor, wortmannin. In vivo, GC resistant neutrophil activation (NE release) was only seen in mice exposed to CS and LPS. In addition, GC refractory MMP-9 expression was only associated with neutrophil activation.<h4>Conclusions</h4>As neutrophils become activated with increasing COPD severity, they become an important source of NE and MMP-9 activity, which secrete proteinases independently of TIMPs. Furthermore, as NE and MMP-9 release was resistant to GC, targeting of the PI3K pathway may offer an alternative pathway to combating this proteinase imbalance in severe COPD.
format	article
author	Ross Vlahos Peter A B Wark Gary P Anderson Steven Bozinovski
author_facet	Ross Vlahos Peter A B Wark Gary P Anderson Steven Bozinovski
author_sort	Ross Vlahos
title	Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
title_short	Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
title_full	Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
title_fullStr	Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
title_full_unstemmed	Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.
title_sort	glucocorticosteroids differentially regulate mmp-9 and neutrophil elastase in copd.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/fa6ada3c0271488baac4d36c250aaa40
work_keys_str_mv	AT rossvlahos glucocorticosteroidsdifferentiallyregulatemmp9andneutrophilelastaseincopd AT peterabwark glucocorticosteroidsdifferentiallyregulatemmp9andneutrophilelastaseincopd AT garypanderson glucocorticosteroidsdifferentiallyregulatemmp9andneutrophilelastaseincopd AT stevenbozinovski glucocorticosteroidsdifferentiallyregulatemmp9andneutrophilelastaseincopd
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Glucocorticosteroids differentially regulate MMP-9 and neutrophil elastase in COPD.

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