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The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD

INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensit...

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Autores principales: Russell, Kirsty E., Chung, Kian Fan, Clarke, Colin J., Durham, Andrew L., Mallia, Patrick, Footitt, Joseph, Johnston, Sebastian L., Barnes, Peter J., Hall, Simon R., Simpson, Karen D., Starkey, Malcolm R., Hansbro, Philip M., Adcock, Ian M., Wiegman, Coen H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709227/
https://www.ncbi.nlm.nih.gov/pubmed/26752192
http://dx.doi.org/10.1371/journal.pone.0146102
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author Russell, Kirsty E.
Chung, Kian Fan
Clarke, Colin J.
Durham, Andrew L.
Mallia, Patrick
Footitt, Joseph
Johnston, Sebastian L.
Barnes, Peter J.
Hall, Simon R.
Simpson, Karen D.
Starkey, Malcolm R.
Hansbro, Philip M.
Adcock, Ian M.
Wiegman, Coen H.
author_facet Russell, Kirsty E.
Chung, Kian Fan
Clarke, Colin J.
Durham, Andrew L.
Mallia, Patrick
Footitt, Joseph
Johnston, Sebastian L.
Barnes, Peter J.
Hall, Simon R.
Simpson, Karen D.
Starkey, Malcolm R.
Hansbro, Philip M.
Adcock, Ian M.
Wiegman, Coen H.
author_sort Russell, Kirsty E.
collection PubMed
description INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD.
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spelling pubmed-47092272016-01-15 The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD Russell, Kirsty E. Chung, Kian Fan Clarke, Colin J. Durham, Andrew L. Mallia, Patrick Footitt, Joseph Johnston, Sebastian L. Barnes, Peter J. Hall, Simon R. Simpson, Karen D. Starkey, Malcolm R. Hansbro, Philip M. Adcock, Ian M. Wiegman, Coen H. PLoS One Research Article INTRODUCTION: Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine associated with acute and chronic inflammatory disorders and corticosteroid insensitivity. Its expression in the airways of patients with chronic obstructive pulmonary disease (COPD), a relatively steroid insensitive inflammatory disease is unclear, however. METHODS: Sputum, bronchoalveolar lavage (BAL) macrophages and serum were obtained from non-smokers, smokers and COPD patients. To mimic oxidative stress-induced COPD, mice were exposed to ozone for six-weeks and treated with ISO-1, a MIF inhibitor, and/or dexamethasone before each exposure. BAL fluid and lung tissue were collected after the final exposure. Airway hyperresponsiveness (AHR) and lung function were measured using whole body plethysmography. HIF-1α binding to the Mif promoter was determined by Chromatin Immunoprecipitation assays. RESULTS: MIF levels in sputum and BAL macrophages from COPD patients were higher than those from non-smokers, with healthy smokers having intermediate levels. MIF expression correlated with that of HIF-1α in all patients groups and in ozone-exposed mice. BAL cell counts, cytokine mRNA and protein expression in lungs and BAL, including MIF, were elevated in ozone-exposed mice and had increased AHR. Dexamethasone had no effect on these parameters in the mouse but ISO-1 attenuated cell recruitment, cytokine release and AHR. CONCLUSION: MIF and HIF-1α levels are elevated in COPD BAL macrophages and inhibition of MIF function blocks corticosteroid-insensitive lung inflammation and AHR. Inhibition of MIF may provide a novel anti-inflammatory approach in COPD. Public Library of Science 2016-01-11 /pmc/articles/PMC4709227/ /pubmed/26752192 http://dx.doi.org/10.1371/journal.pone.0146102 Text en © 2016 Russell et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Russell, Kirsty E.
Chung, Kian Fan
Clarke, Colin J.
Durham, Andrew L.
Mallia, Patrick
Footitt, Joseph
Johnston, Sebastian L.
Barnes, Peter J.
Hall, Simon R.
Simpson, Karen D.
Starkey, Malcolm R.
Hansbro, Philip M.
Adcock, Ian M.
Wiegman, Coen H.
The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title_full The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title_fullStr The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title_full_unstemmed The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title_short The MIF Antagonist ISO-1 Attenuates Corticosteroid-Insensitive Inflammation and Airways Hyperresponsiveness in an Ozone-Induced Model of COPD
title_sort mif antagonist iso-1 attenuates corticosteroid-insensitive inflammation and airways hyperresponsiveness in an ozone-induced model of copd
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709227/
https://www.ncbi.nlm.nih.gov/pubmed/26752192
http://dx.doi.org/10.1371/journal.pone.0146102
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