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dc.contributor.authorMilara, Javier
dc.contributor.authorHernandez, Gracia
dc.contributor.authorBallester, Beatriz
dc.contributor.authorMorell, Anselm
dc.contributor.authorRoger, Inés
dc.contributor.authorMontero, P.
dc.contributor.authorEscrivá, Juan
dc.contributor.authorLloris, José M.
dc.contributor.authorMolina Molina, Maria
dc.contributor.authorMorcillo, Esteban
dc.contributor.authorCortijo, Julio
dc.date.accessioned2018-05-10T18:36:31Z
dc.date.available2018-05-10T18:36:31Z
dc.date.issued2018
dc.identifier.citationMILARA, Javier, et al. The JAK2 pathway is activated in idiopathic pulmonary fibrosis. Respiratory research, 2018, 19.1: 24ca_CA
dc.identifier.issn1465-9921
dc.identifier.issn1465-993X
dc.identifier.urihttp://hdl.handle.net/10234/174625
dc.description.abstractBackground: Idiopathic pulmonary fibrosis (IPF) is the most rapidly progressive and fatal fibrotic disorder, with no curative therapies. The signal transducer and activator of transcription 3 (STAT3) protein is activated in lung fibroblasts and alveolar type II cells (ATII), thereby contributing to lung fibrosis in IPF. Although activation of Janus kinase 2 (JAK2) has been implicated in proliferative disorders, its role in IPF is unknown. The aim of this study was to analyze JAK2 activation in IPF, and to determine whether JAK2/STAT3 inhibition is a potential therapeutic strategy for this disease. Methods and results: JAK2/p-JAK2 and STAT3/pSTAT3 expression was e valuated using quantitative real time-PCR, western blotting, and immunohistochemistry. Compared to human healthy lung tissue ( n = 10) both proteins were upregulated in the lung tissue of IPF patients ( n = 12). Stimulating primary ATII and lung fibroblasts with transforming growth factor beta 1 or interleukin (IL)-6/IL-13 activated JAK2 and STAT3, inducing epithelial to mesenchymal and fibroblast to myofibroblast transitions. Dual p-JAK2/p- STAT3 inhibition with JSI-124 or silencing of JAK2 and STAT3 genes suppressed ATII and the fibroblast to myofibroblast transition, with greater effects than the sum of those obtained using JAK2 or STAT3 inhibitors individually. Dual rather than single inhibition was also more effective for inhibiting fibroblast migration, preventing increases in fibroblast senescence and Bcl-2 expression, and ameliorating impaired autophagy. In rats administ ered JSI-124, a dual inhibitor of p-JAK2/p-STAT3, at a dose of 1 mg/kg/day, bleomycin-induced lung fibrosis was reduced and collagen deposition in the lung was inhibited, as were JAK2 and STAT3 activation and several markers of fibrosi s, autophagy, senescence, and anti-apoptosis. Conclusions: JAK2 and STAT3 are activated in IPF, and their dual inhibition may be an attractive strategy for treating this diseaseca_CA
dc.format.extent12 p.ca_CA
dc.format.mimetypeapplication/pdfca_CA
dc.language.isoengca_CA
dc.publisherBioMed Centralca_CA
dc.relation.isPartOfRespiratory research, 2018, 19.1: 24ca_CA
dc.rights© The Author(s). 2018 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the 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.subjectJAK2ca_CA
dc.subjectSTAT3ca_CA
dc.subjectidiopathic pulmonary fibrosisca_CA
dc.subjectlung fibroblastsca_CA
dc.subjectalveolar type II epithelial cellsca_CA
dc.titleThe JAK2 pathway is activated in idiopathic pulmonary fibrosisca_CA
dc.typeinfo:eu-repo/semantics/articleca_CA
dc.identifier.doihttps://doi.org/10.1186/s12931-018-0728-9
dc.relation.projectIDThis work was supported by grants SAF2014–55322-P (JC), 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 II/2013/014, 2017/023 (JC, EM, JM) “Generalitat Valenciana” and ACIF/2016/341 (BB) from “Generalitat Valenciana”. Funding entities did not contribute to the study design or data collection, analysis and interpretation or writing of the manuscript.ca_CA
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_CA
dc.relation.publisherVersionhttps://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0728-9ca_CA
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_CA


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This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the 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 This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the 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.