臨床上發現，中樞神經與全身性的炎症反應可能是感染腸病毒71 型 (EV71)
後導致神經性肺水腫 (neurogenic pulmonary edema；NPE) 的重要因子。小鼠適應
株EV71/MP4 顱內感染7 日齡ICR 小鼠，在中樞神經可發現無菌性腦膜炎和腦幹
腦炎，並伴隨血清中與NPE 相關之細胞素包括IL-6、IL-10、IL-13 和IFN-γ濃度
暫時性升高；同時EV71 感染小鼠出現後肢癱瘓以及肺功能異常，組織病理學檢
查也發現EV71 感染小鼠死亡前二天發生肺氣腫，但卻沒發生肺水腫。因此，我
們假設EV71 感染中樞神經，伴隨血清中足夠濃度的IL-6、IL-13 和IFN-γ才能引
發NPE。首先，我們給予EV71 感染小鼠腹腔注射IL-6、IL-13 和IFN-γ，與控制
組相比，小鼠在死亡前出現嚴重肺功能異常，及重度肺氣腫和輕微肺水腫，並且
小鼠肺重與體重比顯著增加；只給予EV71 感染小鼠IL-6 與IFN-γ或單獨IL-13
無法得到相同的結果，顯示IL-6、IL-13 和IFN-γ的共同作用在EV71 引起NPE 扮
演重要角色。接著，為了釐清 EV71 感染中樞神經合併細胞素所導致肺部機能惡
化是否為EV71 特有的現象，我們給予第一型單純皰疹病毒 (herpes simplex
virus-1; HSV-1) 感染小鼠腹腔注射IL-6、IL-13 和IFN-γ，小鼠雖出現腦炎和神經
症狀，但沒有肺臟異常加劇或發生NPE。總括而言，本研究證明以外源性IL-6、
IL-13 和IFN-γ注射EV71 感染小鼠可加劇肺臟異常、促進神經性肺水腫發生，且
為EV71 感染所特有的現象。

Clinical observations suggest that both systemic and CNS inflammatory responses
are involved in the induction of neurogenic pulmonary edema (NPE) in enterovirus 71
(EV71) patients. In addition, aseptic meningitis and brainstem encephalitis were noted
in the CNS accompanying with a transient increase of PE-associated cytokines in
serum including IL-6, IL-10, IL-13 and IFN-γ. In an EV71 experimental infectious
model in which 7-day-old mice were intracranially inoculated with a mouse-adapted
EV71 strain MP4, we observed that the animals developed hind-limb paralysis and
pulmonary dysfunction (a marked decrease in peak inspiratory flow, peak of expiratory
flow, minute volume and tidal volume) and emphysema without evidence of NPE a
few days before death. We assumed that the development of EV71-induced NPE may
require a combined effect of CNS infection and a sufficient amount of IL-6, IL-13, and
IFN-γ. We found that EV71-infected mice with post-treatment of IL-6, IL-13, and
IFN-γ developed mild PE and severe emphysema accompanying with a more severe
pulmonary dysfunction than control mice. Post-treatment of EV71-infected mice with
IL-6 and IFN-γ or IL-13 only showed no such effect. Furthermore, in order to check if
this combined effect is specific to EV71-induced encephalitis, we also treated herpes
simplex virus-1 (HSV-1) infected mice with IL-6, IL-13, and IFN-γ, but no such effect
was found. In conclusion, we proved that PE could be induced in EV71-, but not
HSV-1-infected mice with exogenous IL-6, IL-13, and IFN-γ treatment.

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