{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T12:01:18Z","timestamp":1791806478928,"version":"4.3.4"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T00:00:00Z","timestamp":1527811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)\u2013dependent manner. Gas6 (growth arrest\u2013specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Quantitative genomic, proteomic, and functional analyses were used to determine Gas6\/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID\/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule\u2013mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6\/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID\/Bg mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Gas6\/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201707-1519oc","type":"journal-article","created":{"date-parts":[[2018,4,10]],"date-time":"2018-04-10T13:21:02Z","timestamp":1523366462000},"page":"1443-1456","source":"Crossref","is-referenced-by-count":95,"title":["Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis"],"prefix":"10.1093","volume":"197","author":[{"given":"Milena S.","family":"Espindola","sequence":"first","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Habiel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohan","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana L.","family":"Coelho","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne A.","family":"Murray","sequence":"additional","affiliation":[{"name":"Respiratory, Inflammation and Autoimmunity, MedImmune Ltd., Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianhua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W.","family":"Noble","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Hogaboam","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2018,6,1]]},"reference":[{"key":"2026032023204236600_bib1","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1164\/rccm.201306-1141WS","article-title":"Future directions in idiopathic pulmonary fibrosis research. 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