{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:21:19Z","timestamp":1790824879172,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T00:00:00Z","timestamp":1647043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of Taiwan","doi-asserted-by":"publisher","award":["MOST 104-2314-B-075-047"],"award-info":[{"award-number":["MOST 104-2314-B-075-047"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of Taiwan","doi-asserted-by":"publisher","award":["MOST 108-2633-B-009-001"],"award-info":[{"award-number":["MOST 108-2633-B-009-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Health of the United States","award":["R01HL145170"],"award-info":[{"award-number":["R01HL145170"]}]},{"name":"Taiwan Ministry of Health and Welfare","award":["MOHW 106-TDU-B-211-113001"],"award-info":[{"award-number":["MOHW 106-TDU-B-211-113001"]}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V105C-0207"],"award-info":[{"award-number":["V105C-0207"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011912","name":"Taipei Veterans General Hospital","doi-asserted-by":"publisher","award":["V106C-045"],"award-info":[{"award-number":["V106C-045"]}],"id":[{"id":"10.13039\/501100011912","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-\u03b1 treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-\u03b1-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1\u03b2 (IL-1\u03b2) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-\u03baB (NF-\u03baB)\u2013dependent pathway. Linagliptin attenuated tissue factor expression via the Akt\/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.<\/jats:p>","DOI":"10.3390\/ijms23063065","type":"journal-article","created":{"date-parts":[[2022,3,13]],"date-time":"2022-03-13T22:29:43Z","timestamp":1647210583000},"page":"3065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-1282","authenticated-orcid":false,"given":"Shen-Chih","family":"Wang","sequence":"first","affiliation":[{"name":"Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chung-Te","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei 116, Taiwan"},{"name":"Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruey-Hsing","family":"Chou","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen Bouman","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Diabetes Complications and Metabolism, City of Hope, Duarte, CA 91010, USA"},{"name":"Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Hsun","family":"Huang","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shing-Jong","family":"Lin","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan"},{"name":"Division of Cardiology, Heart Center, Cheng-Hsin General Hospital, Taipei 11220, Taiwan"},{"name":"Taipei Heart Institute, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.4049\/jimmunol.177.3.1967","article-title":"Circulating cytokine\/inhibitor profiles reshape the understanding of the SIRS\/CARS continuum in sepsis and predict mortality","volume":"177","author":"Osuchowski","year":"2006","journal-title":"J. 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