{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T11:54:52Z","timestamp":1793447692684,"version":"4.5.0"},"reference-count":48,"publisher":"European Respiratory Society (ERS)","issue":"6","license":[{"start":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T00:00:00Z","timestamp":1654732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Gossamer Bio, Inc."}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2022,5,20]]},"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast\/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR\/CSF1R\/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics\/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416\/Hypoxia (SU5416\/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory\/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416\/H model were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seralutinib potently inhibited PDGFR\u03b1\/\u03b2, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416\/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.02356-2021","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T09:15:12Z","timestamp":1654766112000},"page":"2102356","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":75,"title":["Inhaled seralutinib exhibits potent efficacy in models of pulmonary arterial hypertension"],"prefix":"10.1183","volume":"60","author":[{"given":"Anna","family":"Galkin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravikumar","family":"Sitapara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Clemons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Guimond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura L.","family":"Carter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7196-2379","authenticated-orcid":false,"given":"Ashley","family":"Douthitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Osterhout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneta","family":"Gandjeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Slee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luisa","family":"Salter-Cid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubin M.","family":"Tuder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence S.","family":"Zisman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2022,6,9]]},"reference":[{"key":"2024102102594458000_60.6.2102356.1","doi-asserted-by":"crossref","first-page":"L1115","DOI":"10.1152\/ajplung.00476.2019","article-title":"The hallmarks of severe pulmonary arterial hypertension: the cancer hypothesis\u2013ten years later","volume":"318","author":"Cool","year":"2020","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2024102102594458000_60.6.2102356.2","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1002\/cphy.c100028","article-title":"Inflammatory mechanisms in the pathogenesis of pulmonary arterial hypertension","volume":"1","author":"El Chami","year":"2011","journal-title":"Compr Physiol"},{"key":"2024102102594458000_60.6.2102356.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200806-867ED"},{"key":"2024102102594458000_60.6.2102356.4","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1164\/rccm.201606-1226PP","article-title":"Translational advances in the field of pulmonary hypertension. 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