{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T03:10:04Z","timestamp":1791688204853,"version":"4.3.4"},"reference-count":62,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T00:00:00Z","timestamp":1650585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL123957"],"award-info":[{"award-number":["R01HL123957"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL133951"],"award-info":[{"award-number":["R01HL133951"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL140409"],"award-info":[{"award-number":["R01HL140409"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"publisher","award":["R01HL148810"],"award-info":[{"award-number":["R01HL148810"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["19CDA34500000"],"award-info":[{"award-number":["19CDA34500000"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>There are currently no effective treatments for sepsis and acute respiratory distress syndrome (ARDS). The repositioning of existing drugs is one possible effective strategy for the treatment of sepsis and ARDS. We previously showed that vascular repair and the resolution of sepsis-induced inflammatory lung injury is dependent upon endothelial HIF-1\u03b1\/FoxM1 signaling. The aim of this study was to identify a candidate inducer of HIF-1\u03b1\/FoxM1 signaling for the treatment of sepsis and ARDS. Employing high throughput screening of a library of 1200 FDA-approved drugs by using hypoxia response element (HRE)-driven luciferase reporter assays, we identified Rabeprazole (also known as Aciphex) as a top HIF-\u03b1 activator. In cultured human lung microvascular endothelial cells, Rabeprazole induced HIF1A mRNA expression in a dose-dependent manner. A dose-response study of Rabeprazole in a mouse model of endotoxemia-induced inflammatory lung injury identified a dose that was well tolerated and enhanced vascular repair and the resolution of inflammatory lung injury. Rabeprazole treatment resulted in reductions in lung vascular leakage, edema, and neutrophil sequestration and proinflammatory cytokine expression during the repair phrase. We next used Hif1a\/Tie2Cre knockout mice and Foxm1\/Tie2Cre knockout mice to show that Rabeprazole promoted vascular repair through HIF-1\u03b1\/FoxM1 signaling. In conclusion, Rabeprazole is a potent inducer of HIF-1\u03b1 that promotes vascular repair and the resolution of sepsis-induced inflammatory lung injury via endothelial HIF-1\u03b1\/FoxM1 signaling. This drug therefore represents a promising candidate for repurposing to effectively treat severe sepsis and ARDS.<\/jats:p>","DOI":"10.3390\/cells11091425","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"1425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Rabeprazole Promotes Vascular Repair and Resolution of Sepsis-Induced Inflammatory Lung Injury through HIF-1\u03b1"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9251-357X","authenticated-orcid":false,"given":"Colin E.","family":"Evans","sequence":"first","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Peng","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie M.","family":"Zhu","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-7923","authenticated-orcid":false,"given":"Zhiyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-0339","authenticated-orcid":false,"given":"You-Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA"},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"},{"name":"Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"},{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"},{"name":"Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41572-019-0069-0","article-title":"Acute respiratory distress syndrome","volume":"5","author":"Matthay","year":"2019","journal-title":"Nat. Rev. Dis. 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