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A characteristic of severe SSc\u2010related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>EVs were isolated from normal (NL) or SSc\u2010derived human lungs and primary lung fibroblasts (pLFs). EVs were also isolated from human fibrotic lungs and pLFs induced experimentally with transforming growth factor\u2010\u03b2 (TGF\u03b2). Fibrotic potency of EVs was assessed using functional assays in vitro and in vivo. Transmission electron microscopy, nanoparticle tracking analysis, real\u2010time quantitative polymerase chain reaction\u00a0(RT\u2010qPCR), immunoblotting, and immunofluorescence were used to analyze EVs, their cargo, extracellular matrix (ECM) fractions, and conditioned media.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SSc lungs and pLFs released significantly more EVs than NL lungs, and their EVs showed increased fibrotic content and activity. TGF\u03b2\u2010stimulated NL lung cores and pLFs increased packaging of fibrotic proteins, including fibronectin, collagens, and TGF\u03b2, into released EVs. The EVs induced a fibrotic phenotype in recipient pLFs and in vivo in mouse lungs. Furthermore, EVs interacted with and contributed to the ECM. Finally, suppressing EV release in vivo reduced severity of murine lung fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings highlight EV communication as a novel mechanism for propagation of SSc lung fibrosis. Identifying therapies that reduce EV release, activity, and\/or fibrotic cargo in SSc patient lungs may be a viable therapeutic strategy to improve fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42638","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T15:39:58Z","timestamp":1688139598000},"page":"2228-2239","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Role of Extracellular Vesicles in the Propagation of Lung Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","volume":"75","author":[{"given":"Joe E.","family":"Mouawad","sequence":"first","affiliation":[{"name":"Division of Rheumatology &amp; Immunology, Department of Medicine Medical University of South Carolina and Medical Scientist Training Program, Medical University of South Carolina  Charleston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Sanderson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology &amp; Immunology, Department of Medicine Medical University of South Carolina  Charleston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5746-1447","authenticated-orcid":false,"given":"Shailza","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Rheumatology &amp; Immunology, Department of Medicine Medical University of South Carolina  Charleston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristi L.","family":"Helke","sequence":"additional","affiliation":[{"name":"Departments of Comparative Medicine and Pathology and Laboratory Medicine Medical University of South Carolina  Charleston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph M.","family":"Pilewski","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy &amp; Critical Care Medicine, Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish N.","family":"Nadig","sequence":"additional","affiliation":[{"name":"Division of Organ Transplantation, Department of Surgery Northwestern University Feinberg School of Medicine  Chicago Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-6407","authenticated-orcid":false,"given":"Carol","family":"Feghali\u2010Bostwick","sequence":"additional","affiliation":[{"name":"Division of Rheumatology &amp; 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