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dc.contributor.authorMILARA, JAVIER
dc.contributor.authorMorell, Anselm
dc.contributor.authorde Diego, Alfredo
dc.contributor.authorArtigues, Enrique
dc.contributor.authorMorcillo, Esteban
dc.contributor.authorCortijo, Julio
dc.date.accessioned2019-05-27T07:37:56Z
dc.date.available2019-05-27T07:37:56Z
dc.date.issued2019-01
dc.identifier.citationMILARA, Javier, et al. Mucin 1 deficiency mediates corticosteroid insensitivity in asthma. Allergy, 2019, vol. 74, no 1, p. 111-121ca_CA
dc.identifier.issn0105-4538
dc.identifier.issn1398-9995
dc.identifier.urihttp://hdl.handle.net/10234/182566
dc.description.abstractBACKGROUND: The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma. METHODS: Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL-8, MMP9, and GM-CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines. RESULTS: Mucin 1-CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P < 0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (ρ = -0.71; P < 0.0001). Dexamethasone showed lower anti-inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)-α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1-CT/GRα complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti-inflammatory effects of dexamethasone. CONCLUSION: Mucin 1-CT modulates corticosteroid efficacy in vitro and in vivo asthma models.ca_CA
dc.format.extent11 p.ca_CA
dc.language.isoengca_CA
dc.publisherWileyca_CA
dc.relation.isPartOfAllergy, 2019, vol. 74, no 1ca_CA
dc.rights© EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.ca_CA
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/*
dc.subjectcorticosteroid insensitivityca_CA
dc.subjectMUC1ca_CA
dc.subjectsevere asthmaca_CA
dc.titleMucin 1 deficiency mediates corticosteroid insensitivity in asthmaca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttps://doi.org/10.1111/all.13546
dc.relation.projectIDMinisterio de Ciencia e Innovacion: SAF2015-65368-R; SAF2017-82913-R; TRA2009-0311; Instituto de Salud Carlos III: CB06/06/0027; FIS PI14/01733; FIS PI17/02158; GOBIERNO REGIONAL COMUNIDAD VALENCIANA: Prometeu/2017/023/UVca_CA
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccessca_CA
dc.relation.publisherVersionhttps://onlinelibrary.wiley.com/doi/abs/10.1111/all.13546ca_CA
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_CA


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