Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580
Modulation of inflammation and pathology during dengue virus infection by p38 MAPK inhibitor SB203580
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DOI：
10.1016/j.antiviral.2014.08.004
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发表时间：
2014-10-01
影响因子：
7.6
通讯作者：
Herve, Maxime
中科院分区：
文献类型：
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作者：
Fu, Yilong;Yip, Andy;Herve, Maxime
登革病毒(DENV)感染可导致登革热(DF)、登革出血热(DHF)或登革休克综合征(DSS)。疾病的结果由病毒和宿主因素共同控制。来自DENV感染细胞的炎症介质可能导致血管通透性增加，导致严重的DHF/DSS。因此，抑制炎症可能是治疗登革热患者的一种潜在的治疗方法。在这种背景下，p38MAPK(丝裂原活化蛋白激酶)是调节应激和炎症反应启动的关键酶。我们发现，p38 MAPK抑制剂SB203580抑制了DENV诱导的人PBMC、单核细胞THP-1和粒细胞KU812细胞系过度产生的促炎介质，如TNF-α、IL-8和RANTES。在感染DENV的AG129小鼠中，口服SB203580可防止红细胞压积上升和淋巴细胞减少，限制炎症和病理(包括肠漏)的发展，并显著提高存活率。这些结果首次提供了实验证据，表明短期抑制p38MAPK可能有助于减轻登革热患者的疾病症状。(C)2014爱思唯尔B.V.保留所有权利。
Dengue virus (DENV) infection could lead to dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). The disease outcome is controlled by both viral and host factors. Inflammation mediators from DENV-infected cells could contribute to increased vascular permeability, leading to severe DHF/DSS. Therefore, suppression of inflammation could be a potential therapeutic approach for treatment of dengue patients. In this context, p38 MAPK (mitogen-activated protein kinase) is a key enzyme that modulates the initiation of stress and inflammatory responses. Here we show that SB203580, a p38 MAPK inhibitor, suppressed the over production of DENV-induced pro-inflammatory mediators such as TNF-alpha, IL-8, and RANTES from human PBMCs, monocytic THP-1, and granulocyte KU812 cell lines. Oral administration of SB203580 in DENV-infected AG129 mice prevented hematocrit rise and lymphopenia, limited the development of inflammation and pathology (including intestine leakage), and significantly improved survival. These results, for the first time, have provided experimental evidence to imply that a short term inhibition of p38 MAPK may be beneficial to reduce disease symptoms in dengue patients. (C) 2014 Elsevier B.V. All rights reserved.