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系統識別號 U0026-0812200913590768
論文名稱(中文) 由紅藻氨酸而非腸病毒71型於老鼠所造成的神經損傷引發肺水腫
論文名稱(英文) Neuronal injury induced by kainic acid, but not enterovirus 71, causes pulmonary edema in rodents
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 95
學期 2
出版年 96
研究生(中文) 洪育廷
研究生(英文) Yu-ting Hung
電子信箱 s3693404@mail.ncku.edu.tw
學號 s3693404
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 口試委員-黃阿敏
口試委員-余俊強
指導教授-莊季瑛
中文關鍵字 神經性肺水腫  腸病毒  紅藻氨酸 
英文關鍵字 kainic acid  EV71  neurogenic pulmonary edema 
學科別分類
中文摘要 神經性肺水腫 (neurogenic pulmonary edema, NPE)常快速的發生於中樞神經損傷和腸病毒71型重症感染的病患。先前的動物實驗證實,腸病毒71型所感染的初生幼鼠可見到腦幹中病毒的累積和神經細胞的損傷,但卻不會誘發神經性肺水腫的產生。但有實驗指出,直接注射紅藻胺酸(kainic acid, KA)於腦幹的孤立束核中則可引發神經性肺水腫。臨床上已有研究證實,milrinone (磷酸二酯酶抑制劑),能夠有效的降低腸病毒71型所誘發之肺水腫的致死率。然而,對於腸病毒71型是如何誘發神經性肺水腫,和milrinone對於KA所導致的神經性肺水腫之影響至今仍不甚了解。因此在本研究中,我們探討直接注射腸病毒71型進入成鼠腦幹孤立束核中,是否能誘發神經性肺水腫? 而給予milrinone是否能有效抑制KA所導致的神經性肺水腫? 由結果發現,顱內感染腸病毒後,腸病毒71型明顯地隨時間的增加聚集於腦幹的腹側,而非聚集於注射部位的背側孤立束核。雖然腸病毒71型引起神經損傷,但所有經病毒感染之成鼠均存活且無發現神經性肺水腫的形成。另一方面,注射KA於腦幹孤立束核,不僅造成孤立束核的神經損傷,而且並伴隨著急劇而嚴重的肺水種形成。肺臟組織呈現肺泡壁增厚、鬱血性傷害、水腫液累積及支氣管肺泡灌洗液中蛋白質濃度和介白素6上升,且動物死亡率高達58.3%。因此我們證實了KA而非腸病毒71型注射於腦幹腹側所造成的神經損傷能引發肺水腫的產生。而milrinone的給予能有效的抑制KA所導致的神經損傷、一氧化氮合成酶的活化、介白素-6的上升及神經性肺水腫的形成,進而提高大鼠存活率。以上結果證實,成鼠直接由腦幹感染腸病毒71型的確會造成神經細胞受損,但仍不足以導致神經性肺水腫的形成。我們也發現milrinone可能藉由降低KA所造成的神經損傷以及降低一氧化氮合成酶的活化或是降低介白素6的上升,進而有效的抑制神經性肺水腫的產生。
英文摘要 The neurogenic pulmonary edema (NPE) develops quickly after a variety of cerebral insults and involves in the lethal complication of enterovirus 71 (EV71) infection. Previous studies demonstrated that oral EV71 inoculation in neonatal mice presented a higher mortality and combined with EV71 accumulation and neuronal damage in brainstem, however, there was no NPE development. On the contrary, it had been demonstrated that neuronal damage in nucleus tractus solitarii (NTS) by intracerebral injection of kainic acid (KA) can induce NPE. Furthermore, clinical reports had shown that milrinone, a phosphodiesterase III inhibitor, could reduce the mortality from EV71-induced pulmonary edema. However, the mechanism of EV71 infection induced NPE and the effect of milrinone on KA-induced NPE had not been explored. In the present study, we investigated whether direct inoculation of EV71 into NTS induced NPE in adult mice and whether milrinone treatment can prevent KA-induced pulmonary edema. Our results showed that EV71 time-dependently accumulated in the ventral brainstem rather than in the injection site of NTS after inoculation in adult mice. Although the accumulation of EV71 caused severe neuronal loss in ventral medulla, all animals were survival without any pathological changes in the lung tissue. Moreover, the intracerebral KA injection caused neuronal loss in NTS and a higher mortality rate combined with severe and acute NPE indicated by thickened alveolar septa, congestion, infiltrated edema fluid in alveolar space, and increased IL-6 level and protein concentration in the bronchoalveolar lavage fluid. We further demonstrated that milrinone treatment significantly prevented KA-induced neuronal loss and NPE as well as up-regulation of inducible nitric oxide synthase (iNOS) in NTS and lung tissue. In addition, KA-induced hypertension, neuronal loss and NPE were also occurred by the injection into rostral ventrolateral medulla (RVLM). It indicated that neuronal damage in the ventral medulla caused by KA instead of EV71 induced NPE. Therefore, our results suggested that the neuronal damage caused by direct inoculation EV71 into brainstem is insufficient to cause NPE in adult mice. In addition to clinical application of EV71 infection, we demonstrated that milrinone significantly attenuated KA-induced NPE by the possibility of rescuing neurons from excitotoxity and inhibiting the up-regulation of iNOS and the increase of IL-6.
論文目次 Abstract in English-----------------------------------------------------2
Abstract in Chinese ----------------------------------------------------4
Acknowledgment-------------------------------------------------------6
List of figures-----------------------------------------------------------7
Chapter
1. Introduction--------------------------------------------------------9
2. Material and methods --------------------------------------------18
3. Results -------------------------------------------------------------25
4. Discussion ---------------------------------------------------------31
5. References----------------------------------------------------------39
6. Figures--------------------------------------------------------------45

APPENDIX-----------------------------------------------------------64

About the author------------------------------------------------------67
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