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dc.contributor.authorMilara, Javier
dc.contributor.authorDíaz-Platas, Lucía
dc.contributor.authorContreras, Sonia
dc.contributor.authorRibera, Pilar
dc.contributor.authorRoger, Inés
dc.contributor.authorBallester, Beatriz
dc.contributor.authorMontero, Paula
dc.contributor.authorCogolludo, Ángel
dc.contributor.authorMorcillo, Esteban
dc.contributor.authorCortijo, Julio
dc.date.accessioned2019-04-05T19:14:11Z
dc.date.available2019-04-05T19:14:11Z
dc.date.issued2018
dc.identifier.citationMilara, Javier, et al. "MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease." Respiratory research 19.1 (2018): 226ca_CA
dc.identifier.issn1465-9921
dc.identifier.issn1465-993X
dc.identifier.urihttp://hdl.handle.net/10234/182245
dc.description.abstractBackground Lung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models. Methods MUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models. Results MUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone. Conclusions These results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.ca_CA
dc.format.extent18 p.ca_CA
dc.format.mimetypeapplication/pdfca_CA
dc.language.isoengca_CA
dc.publisherBMCca_CA
dc.relation.isPartOfRespiratory research 19.1 (2018): 226ca_CA
dc.rights© The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.ca_CA
dc.rightsAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectchronic obstructive pulmonary diseaseca_CA
dc.subjectMUC1ca_CA
dc.subjectcorticosteroid resistanceca_CA
dc.titleMUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary diseaseca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttps://doi.org/10.1186/s12931-018-0927-4
dc.relation.projectIDThis work was supported by the grants SAF2017–82913-R (JC), SAF2014–55399-R (AC), FIS PI14/01733 (JM), FIS PI17/02158 (JM), SAF2015–65368-R(EM), CIBERES (CB06/06/0027), TRACE (TRA2009–0311; Spanish Government),and by research grants from the Regional Government Prometeo 2017/023/UV (JC, EM), ACIF/2016/341 (BB), ACIF/2017/A/370 (PR) from“GeneralitatValenciana”.ca_CA
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_CA
dc.relation.publisherVersionhttps://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0927-4ca_CA
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_CA


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© The Author(s). 2018
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Except where otherwise noted, this item's license is described as © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.