{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T21:37:42Z","timestamp":1792532262814,"version":"4.5.0"},"reference-count":76,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","license":[{"start":{"date-parts":[[2021,11,1]],"date-time":"2021-11-01T00:00:00Z","timestamp":1635724800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is a major cause of morbidity and mortality, often as a result of acute respiratory distress syndrome. Respiratory failure is characterized by a hyperinflammatory immune response, lung vascular injury, and edema formation. The potential for immunomodulatory therapy to prevent lung vascular injury and edema formation is not well understood.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results:<\/jats:title>\n            <jats:p>We show that SARS-CoV-2 infection in humanized K18-hACE-2 mice activated inflammatory NLRP3 (NLR family pyrin domain containing 3)\u2013caspase-1 pyroptotic signaling in lungs, release of IL (interleukin)-1\u03b2, and downregulation of the lung endothelial adherens junction protein VE (vascular endothelial)-cadherin. Primary human lung microvascular endothelial cells were susceptible to SARS-CoV-2 infection and displayed pyroptosis-like injury. We observed profound lung vascular injury post\u2013SARS-CoV-2 infection and resultant protein-rich lung edema formation. Selective blockade of IL-1 receptor signaling by IL-1RA (IL-1 receptor antagonist) anakinra prevented downregulation of VE-cadherin, as well as accompanying lung vascular hyperpermeability. IL-1RA also significantly increased survival.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>These results provide insights into the central role of NLRP3\u2013caspase-1 pyroptotic innate immune signaling and loss of lung endothelial adherens junctions in the mechanism of acute respiratory distress syndrome induced by SARS-CoV-2. Our data show that treatment with IL-1RA during activation of inflammasome provides the ideal scenario for preventing lung vascular injury and respiratory failure in coronavirus disease 2019 (COVID-19).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphic Abstract:<\/jats:title>\n            <jats:p>A graphic abstract is available for this article.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.121.316925","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T09:00:15Z","timestamp":1631178015000},"page":"2773-2785","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":41,"title":["Interleukin-1RA Mitigates SARS-CoV-2\u2013Induced Inflammatory Lung Vascular Leakage and Mortality in Humanized K18-hACE-2 Mice"],"prefix":"10.1161","volume":"41","author":[{"given":"Shiqin","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine and the Center for Lung and Vascular Biology (S.X., L.Z., A.S.Q., J.R., A.B.M.), University of Illinois College of Medicine at Chicago."},{"name":"Now with Department of Cardiometabolic Diseases, Merck Research Laboratories, South San Francisco, CA (S.X.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lianghui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine and the Center for Lung and Vascular Biology (S.X., L.Z., A.S.Q., J.R., A.B.M.), University of Illinois College of Medicine at Chicago."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul S.","family":"Qadir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine and the Center for Lung and Vascular Biology (S.X., L.Z., A.S.Q., J.R., A.B.M.), University of Illinois College of Medicine at Chicago."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"Richner","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology (J.M.R., J.C.), University of Illinois College of Medicine at Chicago."},{"name":"Division of Cardiology, Department of Medicine (J.R.), University of Illinois College of Medicine at Chicago."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-5950","authenticated-orcid":true,"given":"Jake","family":"Class","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology (J.M.R., J.C.), University of Illinois College of Medicine at Chicago."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jalees","family":"Rehman","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Regenerative Medicine and the Center for Lung and Vascular Biology (S.X., L.Z., A.S.Q., J.R., A.B.M.), University of 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