| Summary: | 碩士 === 國立成功大學 === 醫事技術學系 === 92 === 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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