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Pathological tissue remodeling in PF is associated with profibrotic changes in the pleural mesothelium and neoangiogenesis within the fibrotic region. However, the factors that promote these processes remain poorly understood. This study investigates the role of extracellular vesicles (EVs) in the development and progression of PF, focusing on mesothelial-to-mesenchymal transition and neoangiogenesis. Human pleural mesothelial cells (HPMCs) were treated with coagulation proteases FXa (factor Xa) and thrombin, and EV production was quantified using nanoparticle tracking analysis. The functional relevance of these EVs was assessed by evaluating their ability to promote a profibrotic phenotype in HPMCs and induce tube formation in endothelial cells. FXa and thrombin treatments significantly increased EV generation from HPMCs via PAR (protease-activated receptor)-mediated cell signaling. Our studies showed that these EVs primed HPMCs toward a profibrotic phenotype and enhanced tube formation in endothelial cells. Further investigations in preclinical mouse models of PF revealed elevated EV levels in pleural fluids from injury-induced mice, compared with saline control mice. In clinical specimens, exudative pleural effusions from patients with empyema and parapneumonic effusions exhibited significantly elevated EV numbers compared with transudative effusions from patients with congestive heart failure. More importantly, EVs isolated from exudative effusions promoted a profibrotic phenotype in naive HPMCs and enhanced tube formation similar to the effects observed with FXa- and thrombin-generated EVs. These findings offer new insights into PF pathogenesis by identifying EVs as previously unknown contributors that modulate mesothelial-to-mesenchymal transition and neoangiogenesis.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0549oc","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T15:19:31Z","timestamp":1750432771000},"page":"938-950","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":4,"title":["Extracellular Vesicles Contribute to the Pathophysiology and Progression of Pleural Fibrosis by Promoting Mesothelial-to-Mesenchymal Transition and Neoangiogenesis"],"prefix":"10.1093","volume":"73","author":[{"given":"Kaushik","family":"Das","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Biology"},{"name":"Biotechnology Research and Innovation Council\u2013National Institute of Biomedical Genomics, Kalyani, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenyi","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Jeffers","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuzi","family":"Owens","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Destarac","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Idell","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology"},{"name":"Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. 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