The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis

Background: 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...

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Autores: Milara, Javier, Hernandez, Gracia, Ballester, Beatriz, Morell, Aanselm, Roger, Inés, Montero, P., Escrivá, Juan, Lloris, José M., Molina Molina, María, Morcillo, Esteban, Cortijo, Julio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/123995
Acceso en línea:https://hdl.handle.net/2445/123995
Access Level:acceso abierto
Palabra clave:Fibrosi pulmonar
Fibroblasts
Cèl·lules epitelials
Pulmonary fibrosis
Epithelial cells
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spelling The Jak2 Pathway Is Activated In Idiopathic Pulmonary FibrosisMilara, JavierHernandez, GraciaBallester, BeatrizMorell, AanselmRoger, InésMontero, P.Escrivá, JuanLloris, José M.Molina Molina, MaríaMorcillo, EstebanCortijo, JulioFibrosi pulmonarFibroblastsCèl·lules epitelialsPulmonary fibrosisFibroblastsEpithelial cellsBackground: 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 evaluated 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 administered 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 fibrosis, 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 disease.Biomed Central Ltd2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/123995Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s12931-018-0728-9Respiratory Research, 2018, Vol. 19:24https://doi.org/10.1186/s12931-018-0728-9cc-by (c) Milara, Javier et al., 2018http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1239952026-05-27T06:46:51Z
dc.title.none.fl_str_mv The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
title The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
spellingShingle The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
Milara, Javier
Fibrosi pulmonar
Fibroblasts
Cèl·lules epitelials
Pulmonary fibrosis
Fibroblasts
Epithelial cells
title_short The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
title_full The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
title_fullStr The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
title_full_unstemmed The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
title_sort The Jak2 Pathway Is Activated In Idiopathic Pulmonary Fibrosis
dc.creator.none.fl_str_mv Milara, Javier
Hernandez, Gracia
Ballester, Beatriz
Morell, Aanselm
Roger, Inés
Montero, P.
Escrivá, Juan
Lloris, José M.
Molina Molina, María
Morcillo, Esteban
Cortijo, Julio
author Milara, Javier
author_facet Milara, Javier
Hernandez, Gracia
Ballester, Beatriz
Morell, Aanselm
Roger, Inés
Montero, P.
Escrivá, Juan
Lloris, José M.
Molina Molina, María
Morcillo, Esteban
Cortijo, Julio
author_role author
author2 Hernandez, Gracia
Ballester, Beatriz
Morell, Aanselm
Roger, Inés
Montero, P.
Escrivá, Juan
Lloris, José M.
Molina Molina, María
Morcillo, Esteban
Cortijo, Julio
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Fibrosi pulmonar
Fibroblasts
Cèl·lules epitelials
Pulmonary fibrosis
Fibroblasts
Epithelial cells
topic Fibrosi pulmonar
Fibroblasts
Cèl·lules epitelials
Pulmonary fibrosis
Fibroblasts
Epithelial cells
description Background: 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 evaluated 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 administered 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 fibrosis, 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 disease.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/123995
url https://hdl.handle.net/2445/123995
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12931-018-0728-9
Respiratory Research, 2018, Vol. 19:24
https://doi.org/10.1186/s12931-018-0728-9
dc.rights.none.fl_str_mv cc-by (c) Milara, Javier et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Milara, Javier et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Biomed Central Ltd
publisher.none.fl_str_mv Biomed Central Ltd
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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