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Injury and sustained inflammation of the pleural space can result in PF, restricting lung expansion and impairing oxygen exchange. During the progression of pleural injury, normal pleural mesothelial cells (PMCs) undergo a transition, termed mesothelial mesenchymal transition (MesoMT). While multiple components of the fibrinolytic pathway have been investigated in pleural remodeling and PF, the role of the urokinase type plasminogen activator receptor (uPAR) is unknown. We found that uPAR is robustly expressed by pleural mesothelial cells in PF. Downregulation of uPAR by siRNA blocked TGF-\u03b2 mediated MesoMT. TGF-\u03b2 was also found to significantly induce uPA expression in PMCs undergoing MesoMT. Like uPAR, uPA downregulation blocked TGF-\u03b2 mediated MesoMT. Further, uPAR is critical for uPA mediated MesoMT. LRP1 downregulation likewise blunted TGF-\u03b2 mediated MesoMT. These findings are consistent with in vivo analyses, which showed that uPAR knockout mice were protected from\n                    <jats:italic>S. pneumoniae<\/jats:italic>\n                    -mediated decrements in lung function and restriction. Histological assessments of pleural fibrosis including pleural thickening and \u03b1-SMA expression were likewise reduced in uPAR knockout mice compared to WT mice. These studies strongly support the concept that uPAR targeting strategies could be beneficial for the treatment of PF.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-99520-5","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T06:04:13Z","timestamp":1635314653000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["TGF-\u03b2 regulation of the uPA\/uPAR axis modulates mesothelial-mesenchymal transition (MesoMT)"],"prefix":"10.1038","volume":"11","author":[{"given":"Ranisha","family":"Logan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Jeffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzi","family":"Owens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prashant","family":"Chauhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuo","family":"Ikebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Idell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torry A.","family":"Tucker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,27]]},"reference":[{"key":"99520_CR1","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/j.1440-1843.2004.00633.x","volume":"9","author":"SE Mutsaers","year":"2004","unstructured":"Mutsaers, S. 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