{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:27:44Z","timestamp":1791203264050,"version":"4.2.0"},"reference-count":53,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:p>\n                    Vascular leakage and its associated phenomena vasodilation and endothelial activation are pathophysiological features of various diseases. Multiple drug candidates targeting these phenomena are in development, necessitating translational models to demonstrate proof\u2010of\u2010pharmacology and proof\u2010of\u2010mechanism in early\u2010phase clinical trials. This single\u2010center experimental study evaluated the intradermal lipopolysaccharide (id LPS) challenge model as a tool to induce and characterize vascular leakage in healthy participants. Eight participants (male:female\u2009=\u20094:4) received id LPS in the volar forearms, followed by serial pharmacodynamic assessments, including imaging and suction blister induction up to 9\u2009hours after injection. Id LPS administration resulted in significant increases in skin perfusion (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001), erythema (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0013), and skin volume (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0008), indicating initial stages of inflammation and fluid extravasation. Blister fluid analysis revealed elevated extravascular concentrations of albumin (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0011), total protein (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001), and neutrophils (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0342), supporting the presence of vascular leakage. Moreover, the expression of endothelial activation markers VCAM\u20101 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0015), ICAM\u20101 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0004), ITGB1 (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.01), and E\u2010selectin (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0218) increased significantly. Disruption of endothelial cell\u2013cell integrity was supported by increased expression of VE\u2010cadherin (\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.0002) in blister fluid. These findings support the applicability of the id LPS model for the induction of vascular leakage in humans. This model holds potential as a translational tool for evaluating the pharmacodynamic responses of vascular leakage\u2010targeting drugs in early clinical development.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70126","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T14:55:38Z","timestamp":1763218538000},"page":"678-687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Breaking Barriers: Characterization of the Intradermal Lipopolysaccharide Challenge as an\n                    <i>In Vivo<\/i>\n                    Model for Controlled Induction of Vascular Leakage in Healthy Volunteers"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3069-4993","authenticated-orcid":false,"given":"Marella Cornelia Elizabeth","family":"van Ruissen","sequence":"first","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2315-8569","authenticated-orcid":false,"given":"Menno","family":"van Diemen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8048-0240","authenticated-orcid":false,"given":"Liza","family":"Botros","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3296-1856","authenticated-orcid":false,"given":"Ingrid","family":"Tomljanovic","sequence":"additional","affiliation":[{"name":"Department of Urology Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hind","family":"Achbo","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4377-6426","authenticated-orcid":false,"given":"Dimitra","family":"Eleftheriou","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8155-9073","authenticated-orcid":false,"given":"Paul Willem","family":"Schenk","sequence":"additional","affiliation":[{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4602-8073","authenticated-orcid":false,"given":"Naomi Bertine","family":"Klarenbeek","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-0844","authenticated-orcid":false,"given":"Derek William","family":"Gilroy","sequence":"additional","affiliation":[{"name":"Department of Experimental &amp; Translational Medicine, Division of Medicine University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9207-1807","authenticated-orcid":false,"given":"Manon Aleida Adriana","family":"Jansen","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8064-8426","authenticated-orcid":false,"given":"Matthijs","family":"Moerland","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research  Leiden The Netherlands"},{"name":"Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23073645"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-012615-044506"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.4161\/viru.25740"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b24-00028"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2006.01.003"},{"key":"e_1_2_10_6_1","unstructured":"ClinicalTrials.gov.Evaluation of the Safety and Efficacy of Razuprotafib in Hospitalized Subjects With Coronavirus Disease 2019 (RESCUE). 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