中文摘要

　　腸病毒71型( Enterovirus 71；EV71)分類上屬於小RNA病毒科( Picornaviridae)，腸病毒屬(Enterovirus genus)；不含外套膜的正股RNA病毒，其基因大小約7.5 kb，臨床症狀主要造成手足口症，而對於三歲以下嬰幼兒則較常併發神經系統病變或肺部發炎浸潤，甚至造成死亡，且腸病毒併發肺水腫的原因除了中樞神經系統病變外，也可能與感染期間誘發過度發炎反應促使細胞分泌過量的細胞激素進而造成肺部細胞的浸潤有關。屬於CXC chemokine的細胞介白素-8 (interleukin-8, IL-8)在過去的文獻中便是一個調節細胞發炎反應的細胞激素，可藉由許多物質所刺激產生，這其中包括：病毒；而在我們的實驗設計中以腸病毒七十一型感染肺部上皮細胞A549來探討在病毒感染的過程中其促細胞分裂原活化蛋白激酶(mitogen-activated protein kinase；MAP Kinase)訊息傳導之途徑對於誘發細胞分泌IL-8的產生所扮演的角色。
　　在我們的實驗結果中利用各種蛋白之抗體包括: anti-Ras、anti-Raf-1、anti-P-MEK、anti-P-ERK及anti-IκB以西方墨點法(Western blotting)證明腸病毒感染A549細胞後可因病毒之外殼蛋白與細胞上之接受器結合後誘發Ras/Raf/MEK/ERK 及其下游的NF-κB 訊息傳導途徑之活化及IL-8的分泌；且分別以ERK及NF-kB訊息傳導之抑制劑-PD98059、Bay11-7802作用於細胞後顯示其會抑制腸病毒71型感染細胞分泌細胞激素IL-8，然而以JNK及p38之抑制劑作用下對於IL-8的誘發則無影響；此外，以病毒斑溶解試驗(Plaque assay)及RT-PCR的結果也顯示若阻止了ERK 傳導路徑的活化同樣也會影響病毒mRNA的合成及病毒的複製能力，因此於我們的實驗中顯示病毒感染後藉由NF-kB及ERK訊息傳導途徑的活化可誘發細胞激素IL-8的產生且增加病毒的感染能力，此可能可進一步解釋腸病毒七十一型感染的患者常併發肺水腫的致病機轉之一。

Abstract

　　Enterovirus 71 (EV71), which belongs to the enterovirus genus within the family Picornaviridae, consists of a non-enveloped capsid surrounding a positive single-stranded RNA genome approximately 7.5 kb in size. EV71 infection can cause not only hand- foot- and- mouth disease or herpangina in children but may also cause progressive sympathetic hyperactivity, pulmonary edema (PE) and/or pulmonary hemorrhage that are associated with severe lung inflammation and neutrophil infiltration. Recent studies showed PE may be caused by increased pulmonary vascular permeability as the result of either brainstem lesions or a systemic inflammatory response caused by the excessive release of cytokines. The CXC chemokine interleukin-8 (IL-8) is an important mediator of the inflammatory response to much stimulation, including viruses. In this study, we explored the role of the mitogen-activated protein kinase (MAPK) pathway in the EV71-associated induction of IL-8 using a model system of A549 epithelial cells. We found that human pulmonary epithelial cells (A549) can induce the Ras/Raf/MEK signal pathways and release IL-8 upon infection with EV71. In addition, EV71 infection also induced a rapid activation of epithelial cell-derived extracellular regulated kinase (ERK), which can be blocked by MEK-specific inhibitor PD98059 and U0126 in dose- and time- dependent manners. Besides MEK-specific inhibitor, pretreatment of A549 cells with NF-kB inhibitors (bay11-7082) can also block the IL-8 production induced by enterovirus 71. However, IL-8 production was not affected by specific inhibitors for p38 MAP kinase (SB202190) and c-jun N-terminal kinase (SP60125). Furthermore, inhibitions of ERK activation by PD98059 prevent viral mRNA synthesis and viral replication. Taken together, these results indicated that EV71-mediated activation of the ERK and NF-kB pathways are causally related to the subsequent production of IL-8, which can contribute to the pathogenesis of pulmonary edema that associated with EV71 infection.

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