{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:23:20Z","timestamp":1781846600688,"version":"3.54.5"},"reference-count":77,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["NO.82002147 and NO.82073618"],"award-info":[{"award-number":["NO.82002147 and NO.82073618"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["NO.2019M662543"],"award-info":[{"award-number":["NO.2019M662543"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Key Scientific Research Project of Henan Institution of Higher Education","award":["NO.20A330004 and NO.21A310026"],"award-info":[{"award-number":["NO.20A330004 and NO.21A310026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sporadic occurrences and outbreaks of hand, foot, and mouth disease (HFMD) caused by Coxsackievirus A2 (CVA2) have frequently reported worldwide recently, which pose a great challenge to public health. Epidemiological studies have suggested that the main cause of death in critical patients is pulmonary edema. However, the pathogenesis of this underlying comorbidity remains unclear. In this study, we utilized the 5-day-old BALB\/c mouse model of lethal CVA2 infection to evaluate lung damage. We found that the permeability of lung microvascular was significantly increased after CVA2 infection. We also observed the direct infection and apoptosis of lung endothelial cells as well as the destruction of tight junctions between endothelial cells. CVA2 infection led to the degradation of tight junction proteins (e.g., ZO-1, claudin-5, and occludin). The gene transcription levels of von Willebrand factor (vWF), endothelin (ET), thrombomodulin (THBD), granular membrane protein 140 (GMP140), and intercellular cell adhesion molecule-1 (ICAM-1) related to endothelial dysfunction were all significantly increased. Additionally, CVA2 infection induced the increased expression of inflammatory cytokines (IL-6, IL-1\u03b2, and MCP-1) and the activation of p38 mitogen-activated protein kinase (MAPK). In conclusion, the disruption of the endothelial barrier contributes to acute lung injury induced by CVA2 infection; targeting p38-MAPK signaling may provide a therapeutic approach for pulmonary edema in critical infections of HFMD.<\/jats:p>","DOI":"10.3390\/ijms22189895","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T21:37:12Z","timestamp":1631569032000},"page":"9895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["The Disruption of the Endothelial Barrier Contributes to Acute Lung Injury Induced by Coxsackievirus A2 Infection in Mice"],"prefix":"10.3390","volume":"22","author":[{"given":"Wangquan","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengdi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-0310","authenticated-orcid":false,"given":"Shuaiyin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7854-4652","authenticated-orcid":false,"given":"Ling","family":"Tao","sequence":"additional","affiliation":[{"name":"School of Public Health, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiguo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-0808","authenticated-orcid":false,"given":"Yuefei","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangcai","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, College of Public Health, Zhengzhou University, Zhengzhou 450001, China"},{"name":"Henan Key Laboratory of Molecular Medicine, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1016\/S1474-4422(10)70209-X","article-title":"Clinical features, diagnosis, and management of enterovirus 71","volume":"9","author":"Ooi","year":"2010","journal-title":"Lancet Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1007\/s00705-020-04734-z","article-title":"Molecular epidemiology of enteroviruses associated with severe hand, foot and mouth disease in Shenzhen, China, 2014\u20132018","volume":"165","author":"Chen","year":"2020","journal-title":"Arch. 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