{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:40:47Z","timestamp":1788784847552,"version":"build-2803163510"},"reference-count":39,"publisher":"Wiley","license":[{"start":{"date-parts":[[2019,4,18]],"date-time":"2019-04-18T00:00:00Z","timestamp":1555545600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000411","name":"Raynaud\u2019s and Scleroderma Association","doi-asserted-by":"crossref","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000411","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000411","name":"Raynaud\u2019s and Scleroderma Association","doi-asserted-by":"crossref","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000411","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000411","name":"Raynaud\u2019s and Scleroderma Association","doi-asserted-by":"crossref","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000411","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000411","name":"Raynaud\u2019s and Scleroderma Association","doi-asserted-by":"crossref","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000411","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Scleroderma Society","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}]},{"name":"Scleroderma Society","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}]},{"name":"Scleroderma Society","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}]},{"name":"Scleroderma Society","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000377","name":"Dunhill Medical Trust","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000377","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation grant","doi-asserted-by":"crossref","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation grant","doi-asserted-by":"crossref","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation grant","doi-asserted-by":"crossref","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation grant","doi-asserted-by":"crossref","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MRC-ABPI COPD-MAP consortium","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}]},{"name":"MRC-ABPI COPD-MAP consortium","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}]},{"name":"MRC-ABPI COPD-MAP consortium","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}]},{"name":"MRC-ABPI COPD-MAP consortium","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000351","name":"British Lung Foundation","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000351","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012147","name":"Royal Brompton and Harefield NHS Foundation Trust","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/100012147","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012147","name":"Royal Brompton and Harefield NHS Foundation Trust","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/100012147","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012147","name":"Royal Brompton and Harefield NHS Foundation Trust","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/100012147","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012147","name":"Royal Brompton and Harefield NHS Foundation Trust","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/100012147","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000761","name":"Imperial College London","doi-asserted-by":"publisher","award":["RG14-10"],"award-info":[{"award-number":["RG14-10"]}],"id":[{"id":"10.13039\/501100000761","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000761","name":"Imperial College London","doi-asserted-by":"publisher","award":["R368\/0714"],"award-info":[{"award-number":["R368\/0714"]}],"id":[{"id":"10.13039\/501100000761","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000761","name":"Imperial College London","doi-asserted-by":"publisher","award":["PG\/14\/27\/30679"],"award-info":[{"award-number":["PG\/14\/27\/30679"]}],"id":[{"id":"10.13039\/501100000761","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000761","name":"Imperial College London","doi-asserted-by":"publisher","award":["G1001367\/1"],"award-info":[{"award-number":["G1001367\/1"]}],"id":[{"id":"10.13039\/501100000761","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["BioMed Research International"],"published-print":{"date-parts":[[2019,4,18]]},"abstract":"<jats:p><jats:italic>Background and Objective<\/jats:italic>. Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-<jats:italic>\u03b2<\/jats:italic> (TGF-<jats:italic>\u03b2<\/jats:italic>) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts.<jats:italic> Methods<\/jats:italic>. In TGF-<jats:italic>\u03b2<\/jats:italic>-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by <jats:italic>\u03b1<\/jats:italic>-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation.<jats:italic> Results and Conclusions<\/jats:italic>. Affymetrix gene array analysis revealed increased<jats:italic> NOX4 <\/jats:italic>and reduced<jats:italic> SOD2 <\/jats:italic>expression in SSc and IPF fibroblasts.<jats:italic> SOD2<\/jats:italic> silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-<jats:italic>\u03b2<\/jats:italic> increased<jats:italic> NOX4<\/jats:italic> and inhibited<jats:italic> SOD2<\/jats:italic> expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-<jats:italic>\u03b2<\/jats:italic>-mediated<jats:italic> NOX4<\/jats:italic>\/<jats:italic>SOD2<\/jats:italic> imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the<jats:italic> NOX4<\/jats:italic> promoter and drive TGF-<jats:italic>\u03b2<\/jats:italic>-induced<jats:italic> NOX4<\/jats:italic> expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.<\/jats:p>","DOI":"10.1155\/2019\/1484736","type":"journal-article","created":{"date-parts":[[2019,4,18]],"date-time":"2019-04-18T23:32:34Z","timestamp":1555630354000},"page":"1-11","source":"Crossref","is-referenced-by-count":29,"title":["Bromodomain and Extraterminal (BET) Protein Inhibition Restores Redox Balance and Inhibits Myofibroblast Activation"],"prefix":"10.1155","volume":"2019","author":[{"given":"Carmel J. W.","family":"Stock","sequence":"first","affiliation":[{"name":"Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4107-4028","authenticated-orcid":true,"given":"Charalambos","family":"Michaeloudes","sequence":"additional","affiliation":[{"name":"Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Leoni","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Durham","sequence":"additional","affiliation":[{"name":"Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Mumby","sequence":"additional","affiliation":[{"name":"Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athol U.","family":"Wells","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kian Fan","family":"Chung","sequence":"additional","affiliation":[{"name":"Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2101-8843","authenticated-orcid":true,"given":"Ian M.","family":"Adcock","sequence":"additional","affiliation":[{"name":"Airway Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta A.","family":"Renzoni","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela E.","family":"Lindahl","sequence":"additional","affiliation":[{"name":"Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Sydney Street, London SW3 6NP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38390"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2006.066068"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2006.062836"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1378\/chest.06-2568"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1097\/mcp.0b013e328356800f"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199411103311907"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2012.10.003"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m112.431973"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.51.30334"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2007.07.006"},{"key":"11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/1465-9921-6-11","volume":"6","year":"2005","journal-title":"Respiratory Research"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-011-1695-4"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200111)44:11<2653::AID-ART445>3.0.CO;2-1"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.100398"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.5.9803102"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1016\/s0891-5849(99)00035-0"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2362.2006.01636.x"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1016\/j.pupt.2006.10.005"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2005.03.023"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2005"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2009.113456"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.109.916098"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1017\/s1462399411001992"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.081661"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.04.020"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.20.15220"},{"key":"27","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/1465-9921-14-80","volume":"14","year":"2013","journal-title":"Respiratory Research"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301984"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00090.2010"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2015.12.45"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2016.12.031"},{"issue":"2","key":"33","volume":"8","year":"2017","journal-title":"Cell Death & Disease"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00134.2010"},{"key":"35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq718"},{"key":"36","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1901"},{"key":"37","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4240"},{"issue":"4","key":"38","volume":"5","year":"2014","journal-title":"Cell Death & Disease"},{"key":"39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308347100"}],"container-title":["BioMed Research International"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2019\/1484736.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2019\/1484736.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/bmri\/2019\/1484736.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T06:15:22Z","timestamp":1590041722000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/bmri\/2019\/1484736\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,18]]},"references-count":39,"alternative-id":["1484736","1484736"],"URL":"https:\/\/doi.org\/10.1155\/2019\/1484736","relation":{},"ISSN":["2314-6133","2314-6141"],"issn-type":[{"value":"2314-6133","type":"print"},{"value":"2314-6141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,18]]}}}