{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:19:48Z","timestamp":1790767188670,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2016,1,25]],"date-time":"2016-01-25T00:00:00Z","timestamp":1453680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"MedImmune, LLC"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Systemic sclerosis (SSc) is a fibrotic disease characterized by an obliterative vasculopathy with thrombosis and impairment of the coagulation\u2013fibrinolysis balance. Plasminogen activator inhibitor 1 (PAI\u20101) is the major inhibitor of profibrinolytic plasminogen activators (PAs). This study was undertaken to evaluate the contribution of PAI\u20101 to SSc pathology in the skin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PAI\u20101 was evaluated in skin from patients with diffuse SSc (dSSc) and those with limited SSc (lSSc) by immunohistochemistry. The contribution of PAI\u20101 to SSc pathology was tested in vivo in murine graft\u2010versus\u2010host disease (GVHD) and bleomycin models of progressive skin fibrosis and in vitro in dermal human microvascular endothelial cells (HMVECs) using a monoclonal antibody that selectively prevents the binding of PAI\u20101 to PA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Skin from patients with dSSc and those with lSSc showed increased PAI\u20101 levels in the epidermis and microvessel endothelium. PAI\u20101 neutralization in the GVHD model led to a dramatic, dose\u2010dependent improvement in clinical skin score, concomitant with vasculopathy resolution, including a reduction in fibrinolysis regulators and vascular injury markers, as well as reduced inflammation. Resolution of vasculopathy and inflammation was associated with resolution of skin fibrosis, as assessed by reduction in collagen content and expression of key profibrotic mediators, including transforming growth factor \u03b21 and tissue inhibitor of metalloproteinases 1. Similar to the GVHD model, PAI\u20101 neutralization reduced dermal inflammation and fibrosis in the bleomycin model. PAI\u20101 neutralization stimulated plasmin\u2010mediated metalloproteinase 1 activation in dermal HMVECs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that neutralization of the antifibrinolytic function of PAI\u20101 resolves skin fibrosis by limiting the extent of initial vascular injury and connective tissue inflammation. These data suggest that PAI\u20101 represents an important checkpoint in disease pathology in human SSc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39443","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T12:49:28Z","timestamp":1443444568000},"page":"473-483","source":"Crossref","is-referenced-by-count":39,"title":["Resolution of Skin Fibrosis by Neutralization of the Antifibrinolytic Function of Plasminogen Activator Inhibitor 1"],"prefix":"10.1002","volume":"68","author":[{"given":"Rapha\u00ebl","family":"Lemaire","sequence":"first","affiliation":[{"name":"MedImmune LLC, Gaithersburg, Maryland, and Boston University School of Medicine Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Burwell","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Sun","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Delaney","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bakken","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Cheng","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlon C.","family":"Rebelatto","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meggan","family":"Czapiga","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"de\u2010Mendez","sequence":"additional","affiliation":[{"name":"MedImmune, Ltd. Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony J.","family":"Coyle","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Herbst","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Lafyatis","sequence":"additional","affiliation":[{"name":"Boston University School of Medicine  Boston Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Connor","sequence":"additional","affiliation":[{"name":"MedImmune LLC Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,25]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"1643","volume-title":"Arthritis and allied Conditions: a textbook of rheumatology","author":"Korn J.","year":"2001"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/36.10.1045"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1182\/blood.V83.2.351.351","article-title":"Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor\u20101\u2010dependent and \u2010independent mechanisms","volume":"83","author":"Fay WP","year":"1994","journal-title":"Blood"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199212103272406"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111559"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.16.4.539"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1655998"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5922.2010.00171.x"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804257200"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000042231.04318.E6"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.189514"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/0955-0674(89)90068-9"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.8.2632"},{"key":"e_1_2_7_15_1","unstructured":"VousdenKA PopovicB LundqvistT NaimanB CarruthersAM NewtonP et al.Molecular basis for the potent inhibition of plasminogen activator inhibitor\u20101 by a monoclonal antibody. Submitted for publication."},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38098"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27220"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.20160"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2005.04979.x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.7.794"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.9.2585"},{"key":"e_1_2_7_22_1","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1055\/s-0037-1614532","article-title":"Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury","volume":"81","author":"Matsuno H","year":"1999","journal-title":"Thromb Haemost"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000031162.80988.2B"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.10.1002"},{"key":"e_1_2_7_25_1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1182\/blood.V96.1.153","article-title":"Vascular release of plasminogen activator inhibitor\u20101 impairs fibrinolysis during acute arterial thrombosis in mice","volume":"96","author":"Kawasaki T","year":"2000","journal-title":"Blood"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-2681"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119148"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000019360.14554.53"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63949-1"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000201087.23877.e1"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2003.00533.x"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.3.1664"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken370"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10042"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39443","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.39443","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T14:49:06Z","timestamp":1759934946000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.39443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,25]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2016,2]]}},"alternative-id":["10.1002\/art.39443"],"URL":"https:\/\/doi.org\/10.1002\/art.39443","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,25]]}}}