{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:11:11Z","timestamp":1790791871394,"version":"4.1.0"},"reference-count":43,"publisher":"European Respiratory Society (ERS)","issue":"1","funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2017,10,14]]},"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Pleural effusion is a frequent side-effect of dasatinib, a second-generation tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukaemia. However, the underlying mechanisms remain unknown. We hypothesised that dasatinib alters endothelial integrity, resulting in increased pulmonary vascular endothelial permeability and pleural effusion.<\/jats:p><jats:p>To test this, we established the first animal model of dasatinib-related pleural effusion, by treating rats with a daily regimen of high doses of dasatinib (10\u2005mg\u00b7kg<jats:sup>\u22121<\/jats:sup>\u00b7day<jats:sup>\u22121<\/jats:sup>for 8\u2005weeks).<\/jats:p><jats:p>Pleural ultrasonography revealed that rats chronically treated with dasatinib developed pleural effusion after 5\u2005weeks. Consistent with these<jats:italic>in vivo<\/jats:italic>observations, dasatinib led to a rapid and reversible increase in paracellular permeability of human pulmonary endothelial cell monolayers as reflected by increased macromolecule passage, loss of vascular endothelial cadherin and zonula occludens-1 from cell\u2013cell junctions, and the development of actin stress fibres. These results were replicated using human umbilical vein endothelial cells and confirmed by decreased endothelial resistance. Interestingly, we demonstrated that this increased endothelial permeability is a reactive oxygen species (ROS)-dependent mechanism<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>using a cotreatment with an antioxidant agent,<jats:italic>N<\/jats:italic>-acetylcysteine.<\/jats:p><jats:p>This study shows that dasatinib alters pulmonary endothelial permeability in a ROS-dependent manner<jats:italic>in vitro<\/jats:italic>and<jats:italic>in vivo<\/jats:italic>leading to pleural effusion.<\/jats:p>","DOI":"10.1183\/13993003.01096-2017","type":"journal-article","created":{"date-parts":[[2018,1,19]],"date-time":"2018-01-19T01:10:49Z","timestamp":1516324249000},"page":"1701096","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":74,"title":["Dasatinib increases endothelial permeability leading to pleural effusion"],"prefix":"10.1183","volume":"51","author":[{"given":"Carole","family":"Phan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne-Marie","family":"Jutant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2336-5099","authenticated-orcid":false,"given":"Ly","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00ebl","family":"Thuillet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Seferian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-6922","authenticated-orcid":false,"given":"David","family":"Montani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8545-747X","authenticated-orcid":false,"given":"Alice","family":"Huertas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan van","family":"Bezu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"Breijer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton Vonk","family":"Noordegraaf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0703-2892","authenticated-orcid":false,"given":"Marc","family":"Humbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurjan","family":"Aman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8545-4452","authenticated-orcid":false,"given":"Christophe","family":"Guignabert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2018,1,18]]},"reference":[{"key":"2024101909232914000_51.1.1701096.1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24423"},{"key":"2024101909232914000_51.1.1701096.2","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2020"},{"key":"2024101909232914000_51.1.1701096.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200705-715CR"},{"key":"2024101909232914000_51.1.1701096.4","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.12.0329"},{"key":"2024101909232914000_51.1.1701096.5","first-page":"85","article-title":"Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure\u2013response analysis of a Phase III study","volume":"5","author":"Wang","year":"2013","journal-title":"Clin Pharmacol"},{"key":"2024101909232914000_51.1.1701096.6","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2008.07108.x"},{"key":"2024101909232914000_51.1.1701096.7","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-011-0921-9"},{"key":"2024101909232914000_51.1.1701096.8","doi-asserted-by":"publisher","DOI":"10.1097\/MCP.0b013e32832af07c"},{"key":"2024101909232914000_51.1.1701096.9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI86249"},{"key":"2024101909232914000_51.1.1701096.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64828-6"},{"key":"2024101909232914000_51.1.1701096.11","first-page":"2912","article-title":"Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions","volume":"53","author":"Yeo","year":"1993","journal-title":"Cancer Res"},{"key":"2024101909232914000_51.1.1701096.12","first-page":"957","article-title":"Treatment for malignant pleural effusion of human lung adenocarcinoma by inhibition of vascular endothelial growth factor receptor tyrosine kinase phosphorylation","volume":"6","author":"Yano","year":"2000","journal-title":"Clin Cancer Res"},{"key":"2024101909232914000_51.1.1701096.13","first-page":"L1057","article-title":"Endothelial permeability and IL-6 production during hypoxia: role of ROS in signal transduction","volume":"277","author":"Ali","year":"1999","journal-title":"Am J Physiol"},{"key":"2024101909232914000_51.1.1701096.14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085246"},{"key":"2024101909232914000_51.1.1701096.15","doi-asserted-by":"publisher","DOI":"10.2741\/3223"},{"key":"2024101909232914000_51.1.1701096.16","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2126"},{"key":"2024101909232914000_51.1.1701096.17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-491423"},{"key":"2024101909232914000_51.1.1701096.18","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.071555"},{"key":"2024101909232914000_51.1.1701096.19","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.101444"},{"key":"2024101909232914000_51.1.1701096.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2007.07.002"},{"key":"2024101909232914000_51.1.1701096.21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.vph.2015.03.017","article-title":"ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension","volume":"70","author":"Beckers","year":"2015","journal-title":"Vascul Pharmacol"},{"key":"2024101909232914000_51.1.1701096.22","doi-asserted-by":"publisher","DOI":"10.1038\/40187"},{"key":"2024101909232914000_51.1.1701096.23","doi-asserted-by":"publisher","DOI":"10.1517\/17425255.2010.506873"},{"key":"2024101909232914000_51.1.1701096.24","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.108.025932"},{"key":"2024101909232914000_51.1.1701096.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2012.04.010"},{"key":"2024101909232914000_51.1.1701096.26","first-page":"L284","article-title":"Oxidants affect permeability and repair of the cultured human tracheal epithelium","volume":"268","author":"Yamaya","year":"1995","journal-title":"Am J Physiol"},{"key":"2024101909232914000_51.1.1701096.27","doi-asserted-by":"publisher","DOI":"10.3109\/01902149709046044"},{"key":"2024101909232914000_51.1.1701096.28","first-page":"L681","article-title":"KGF prevents hydrogen peroxide-induced increases in airway epithelial cell permeability","volume":"272","author":"Waters","year":"1997","journal-title":"Am J Physiol"},{"key":"2024101909232914000_51.1.1701096.29","doi-asserted-by":"publisher","DOI":"10.1038\/nri3423"},{"key":"2024101909232914000_51.1.1701096.30","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/cam4.1019","article-title":"Dasatinib inhibits actin fiber reorganization and promotes endothelial cell permeability through RhoA\u2013ROCK pathway","volume":"6","author":"Dasgupta","year":"2017","journal-title":"Cancer Med"},{"key":"2024101909232914000_51.1.1701096.31","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1159\/000375484","article-title":"Tyrosine kinase inhibitor induced isolated pericardial effusion","volume":"8","author":"Agrawal","year":"2015","journal-title":"Case Rep Oncol"},{"key":"2024101909232914000_51.1.1701096.32","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa062867"},{"key":"2024101909232914000_51.1.1701096.33","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-07-513937"},{"key":"2024101909232914000_51.1.1701096.34","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01410-2016"},{"key":"2024101909232914000_51.1.1701096.35","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00323.2014"},{"key":"2024101909232914000_51.1.1701096.36","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.134304"},{"key":"2024101909232914000_51.1.1701096.37","doi-asserted-by":"publisher","DOI":"10.1042\/bj20011804"},{"key":"2024101909232914000_51.1.1701096.38","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1242\/jcs.108.2.609","article-title":"Evidence that tyrosine phosphorylation may increase tight junction permeability","volume":"108","author":"Staddon","year":"1995","journal-title":"J Cell Sci"},{"key":"2024101909232914000_51.1.1701096.39","first-page":"F514","article-title":"Increased Tyr phosphorylation of ZO-1 during modification of tight junctions between glomerular foot processes","volume":"268","author":"Kurihara","year":"1995","journal-title":"Am J Physiol"},{"key":"2024101909232914000_51.1.1701096.40","doi-asserted-by":"publisher","DOI":"10.1247\/csf.20.387"},{"key":"2024101909232914000_51.1.1701096.41","doi-asserted-by":"crossref","first-page":"49699","DOI":"10.18632\/oncotarget.10435","article-title":"Dasatinib-loaded albumin nanoparticles possess diminished endothelial cell barrier disruption and retain potent anti-leukemia cell activity","volume":"7","author":"Dong","year":"2016","journal-title":"Oncotarget"},{"key":"2024101909232914000_51.1.1701096.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2003.09.007"},{"key":"2024101909232914000_51.1.1701096.43","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00393.2015"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.01096-2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T06:49:24Z","timestamp":1740379764000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.01096-2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,1,18]]},"published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1183\/13993003.01096-2017"],"URL":"https:\/\/doi.org\/10.1183\/13993003.01096-2017","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]}}}