{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T02:40:22Z","timestamp":1789008022959,"version":"build-2803163510"},"reference-count":64,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":57,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["Z01-AI-001083"],"award-info":[{"award-number":["Z01-AI-001083"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,15]]},"abstract":"<jats:p>\n                    Clarkson disease, or monoclonal gammopathy\u2013associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of\n                    <jats:italic>N<\/jats:italic>\n                    (\u03b3)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL\/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.\n                  <\/jats:p>","DOI":"10.1172\/jci169137","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T12:00:41Z","timestamp":1710849641000},"source":"Crossref","is-referenced-by-count":10,"title":["Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease"],"prefix":"10.1172","volume":"134","author":[{"given":"Ararat J.","family":"Ablooglu","sequence":"first","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Sheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihui","family":"Xie","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek","family":"Desai","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subrata","family":"Paul","sequence":"additional","affiliation":[{"name":"Integrative Data Sciences Section, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin B.","family":"Lack","sequence":"additional","affiliation":[{"name":"Integrative Data Sciences Section, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda A.","family":"Scott","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Robin","family":"Eisch","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadiusz Z.","family":"Dudek","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1038-981X","authenticated-orcid":true,"given":"Samir M.","family":"Parikh","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk M.","family":"Druey","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2017.07.021"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0000000000002496"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2014.08.015"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2017.05.023"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2022.07.006"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2020.03.057"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.14381"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-022-03587-1"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.10.042"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-019-0647-4"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0133266"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1534\/g3.119.400740"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4161\/rdis.27445"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2230"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.930683"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.anndiagpath.2022.152028"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4309"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2022.948541"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/path.5023"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.122043"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-08-375816"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201310-1746LE"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2020.11.006"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201800841R"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.582"},{"key":"B26","article-title":"Inflammatory markers of the systemic capillary leak syndrome (Clarkson disease)","volume":"5","author":"Xie","year":"2014","journal-title":"J Clin Cell Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1159\/000514314"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14522"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1159\/000231796"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.11.003"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2016.01.034"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/advs.201901166"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.108688"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.253179"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2015.10.048"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7598-3_12"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106302200"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.427765"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq077"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.06.063"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.967909"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8688"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1519467113"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf5537"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.3323"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162143"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001254"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.64944"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000216044.49494.c4"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.06.003"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-019-1192-x"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-19-0218"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-197705000-00004"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3201\/eid2710.211155"},{"key":"B55","article-title":"Systemic capillary leak syndrome: is methylene blue the silver bullet?","volume":"2014","author":"Umbrello","year":"2014","journal-title":"Case Rep Crit Care"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu314"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1093\/gigascience\/giab008"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4235"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaa1081"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2308-7"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1016"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1200\/CCI.19.00132"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.10.007"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/169137\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:30:35Z","timestamp":1779233435000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/169137"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,19]]},"references-count":64,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,4,4]]},"published-print":{"date-parts":[[2024,5,15]]}},"alternative-id":["10.1172\/JCI169137"],"URL":"https:\/\/doi.org\/10.1172\/jci169137","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,19]]},"article-number":"e169137"}}