{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T22:19:58Z","timestamp":1783635598860,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,13]],"date-time":"2019-10-13T00:00:00Z","timestamp":1570924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 105-2314-B-038-055-MY2"],"award-info":[{"award-number":["MOST 105-2314-B-038-055-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 106-2320-B-038-060-MY2"],"award-info":[{"award-number":["MOST 106-2320-B-038-060-MY2"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taipei Medical University\u2013Taipei Medical University Hospital","award":["105 TMU-TMUH-02-02"],"award-info":[{"award-number":["105 TMU-TMUH-02-02"]}]},{"DOI":"10.13039\/501100010613","name":"Taipei Medical University Hospital","doi-asserted-by":"publisher","award":["107IIT06"],"award-info":[{"award-number":["107IIT06"]}],"id":[{"id":"10.13039\/501100010613","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Thrombin is an essential procoagulant and profibrotic mediator. However, its implication in tuberculous pleural effusion (TBPE) remains unknown. The effusion thrombin and plasminogen activator inhibitor-1 (PAI-1) levels were measured among transudative pleural effusion (TPE, n = 22) and TBPE (n = 24) patients. Pleural fibrosis, identified as radiological residual pleural thickening (RPT) and shadowing, was measured at 12-month follow-up. Moreover, in vivo and in vitro effects of thrombin on PAI-1 expression and mesothelial\u2013mesenchymal transition (MMT) were assessed. We demonstrated the effusion thrombin levels were significantly higher in TBPE than TPE, especially greater in TBPE patients with RPT &gt; 10mm than those without, and correlated positively with PAI-1 and pleural fibrosis area. In carbon black\/bleomycin-treated mice, knockdown of protease-activated receptor-1 (PAR-1) markedly downregulated \u03b1-smooth muscle actin (\u03b1-SMA) and fibronectin, and attenuated pleural fibrosis. In pleural mesothelial cells (PMCs), thrombin concentration-dependently increased PAI-1, \u03b1-SMA, and collagen I expression. Specifically, Mycobacterium tuberculosis H37Ra (MTBRa) induced thrombin production by PMCs via upregulating tissue factor and prothrombin, and PAR-1 silencing considerably abrogated MTBRa\u2212stimulated PAI-1 expression and MMT. Consistently, prothrombin\/PAR-1 expression was evident in the pleural mesothelium of TBPE patients. Conclusively, thrombin upregulates PAI-1 and MMT and may contribute to tuberculous pleural fibrosis. Thrombin\/PAR-1 inhibition may confer potential therapy for pleural fibrosis.<\/jats:p>","DOI":"10.3390\/ijms20205076","type":"journal-article","created":{"date-parts":[[2019,10,14]],"date-time":"2019-10-14T03:54:13Z","timestamp":1571025253000},"page":"5076","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Thrombin Upregulates PAI-1 and Mesothelial\u2013Mesenchymal Transition Through PAR-1 and Contributes to Tuberculous Pleural Fibrosis"],"prefix":"10.3390","volume":"20","author":[{"given":"Cheng-Ying","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-3678","authenticated-orcid":false,"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nursing, Mackay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie-Heng","family":"Tsai","sequence":"additional","affiliation":[{"name":"School of Nutrition and Health Sciences, College of Public Health and Nutrition, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-976X","authenticated-orcid":false,"given":"Chi-Li","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan"},{"name":"Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,13]]},"reference":[{"key":"ref_1","unstructured":"GBD Tuberculosis Collaborators (2018). 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