Contribution of neutrophil-derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection
Contribution of neutrophil-derived myeloperoxidase in the early phase of fulminant acute respiratory distress syndrome induced by influenza virus infection
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DOI：
10.1111/j.1348-0421.2011.00424.x
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发表时间：
2012-03-01
影响因子：
2.6
通讯作者：
Suzuki, Kazuo
中科院分区：
文献类型：
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作者：
Sugamata, Ryuichi;Dobashi, Hideki;Suzuki, Kazuo
由于流感病毒感染引起的急性呼吸窘迫综合征（ARDS）的发病机制尚不清楚，我们只能改进现有的治疗干预措施。为了探讨这一主题，我们使用PR-8（A/H1N1）感染的小鼠模型研究了流感诱导的ARDS中细胞因子和急性肺损伤因素的免疫病因学。感染的小鼠表现为暴发性严重肺炎，伴有白细胞浸润、紧密连接上的claudin改变和透明膜形成。除IFN-α外，支气管肺泡灌洗液（BALF）中还大量释放角质形成细胞趋化因子（KC）、巨噬细胞炎性蛋白2（MIP-2）、调节活化正常T细胞表达和分泌的因子（RANTES）和单核细胞趋化蛋白1（MCP-1）。我们专注于中性粒细胞髓过氧化物酶（MPO）作为一种有效的组织损伤因子，并通过使用基因缺乏MPO的小鼠来检查其在流感肺炎中的作用。MPO的缺乏减少了炎性损伤，抑制了与肺中claudins改变相关的总BALF蛋白的泄漏。MPO-/-小鼠还抑制了肺中的病毒载量。目前的研究表明，MPO介导的OCl-产生影响claudin分子，并导致蛋白质渗漏和病毒传播作为流感诱导的ARDS的损伤因素。
Because the pathogenesis of acute respiratory distress syndrome (ARDS) induced by influenza virus infection remains unknown, we can only improve on existing therapeutic interventions. To approach the subject, we investigated immunological etiology focused on cytokines and an acute lung damage factor in influenza-induced ARDS by using a PR-8 (A/H1N1)-infected mouse model. The infected mouse showed fulminant severe pneumonia with leukocyte infiltration, claudin alteration on tight junctions, and formation of hyaline membranes. In addition to interferon (IFN)-a, plenty of keratinocyte-derived chemokines (KC), macrophage inflammatory protein 2 (MIP-2), regulated on activation normal T-cell expressed and secreted (RANTES), and monocyte chemotactic protein 1 (MCP-1) were significantly released into bronchoalveolar lavage fluid (BALF) of the model. We focused on neutrophil myeloperoxidase (MPO) as a potent tissue damage factor and examined its contribution in influenza pneumonia by using mice genetically lacking in MPO. The absence of MPO reduced inflammatory damage with suppression of leakage of total BALF proteins associated with alteration of claudins in the lung. MPO-/- mice also suppressed viral load in the lung. The present study suggests that MPO-mediated OCl- generation affects claudin molecules and leads to protein leakage and viral spread as a damage factor in influenza-induced ARDS.