Influenza Virus-Cytokine-Protease Cycle in the Pathogenesis of Vascular Hyperpermeability in Severe Influenza
Influenza Virus-Cytokine-Protease Cycle in the Pathogenesis of Vascular Hyperpermeability in Severe Influenza
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DOI：
10.1086/656044
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发表时间：
2010-10-01
影响因子：
6.4
通讯作者：
Kido, Hiroshi
中科院分区：
文献类型：
--
作者：
Wang, Siye;Le, Trong Quang;Kido, Hiroshi
背景严重流感的特征是细胞因子风暴和多器官衰竭伴水肿。本研究的目的是明确细胞因子风暴对重症流感患者血管通透性增高发病机制的影响。用甲型流感WSN/33（H1N1）病毒感染断奶小鼠。在肺、脑、心脏和培养的人脐静脉内皮细胞中分析促炎细胞因子、肿瘤坏死因子（TNF）α、白细胞介素（IL）6、IL-1 β和胰蛋白酶的水平。检测转录抑制剂对细胞因子和胰蛋白酶表达及病毒复制的影响。在感染的前6天，甲型流感病毒感染导致TNF-α、IL-6、IL-1 β、病毒血凝素加工蛋白酶胰蛋白酶水平和病毒复制显著增加，伴有肺和脑中血管通透性过高。胰蛋白酶上调被抑制的转录抑制细胞因子在体内和抗细胞因子抗体在内皮细胞。蛋白酶激活受体2拮抗剂和胰蛋白酶促剂可抑制与精氨酸和胰蛋白酶诱导的内皮细胞高通透性相关的钙动员和紧密连接成分闭合小带-1的丢失。流感病毒-细胞因子-蛋白酶循环是重症流感血管通透性增高的关键机制之一。
Background. Severe influenza is characterized by cytokine storm and multiorgan failure with edema. The aim of this study was to define the impact of the cytokine storm on the pathogenesis of vascular hyperpermeability in severe influenza.Methods. Weanling mice were infected with influenza A WSN/33(H1N1) virus. The levels of proinflammatory cytokines, tumor necrosis factor (TNF) alpha, interleukin (IL) 6, IL-1 beta, and trypsin were analyzed in the lung, brain, heart, and cultured human umbilical vein endothelial cells. The effects of transcriptional inhibitors on cytokine and trypsin expressions and viral replication were determined.Results. Influenza A virus infection resulted in significant increases in TNF-alpha, IL-6, IL-1 beta, viral hemagglutinin-processing protease trypsin levels, and viral replication with vascular hyperpermeability in lung and brain in the first 6 days of infection. Trypsin upregulation was suppressed by transcriptional inhibition of cytokines in vivo and by anti-cytokine antibodies in endothelial cells. Calcium mobilization and loss of tight junction constituent, zonula occludens-1, associated with cytokine-and trypsin-induced endothelial hyperpermeability were inhibited by a protease-activated receptor-2 antagonist and a trypsin inhibitor.Conclusions. The influenza virus-cytokine-protease cycle is one of the key mechanisms of vascular hyperpermeability in severe influenza.