臺灣博碩士論文加值系統

1998年腸病毒71型的流行造成台灣許多病童的死亡。在重症患者身上，常可觀察到三種病徵同時存在，包括腦幹炎、肺水腫、以及心臟衰竭。由於此種病人的胸部X光心臟影像不大，而且心臟病理檢查也看不到心肌炎的現象，故常被臨床醫師誤以為心臟正常。過去的研究大多認為病人是死於肺水腫，而且認為是神經性引起的肺水腫，然而他們並沒有仔細檢查病人的心臟功能。作者仔細觀察病人的臨床表現發現，病人在發生心臟衰竭之前都有交感神經過度興奮的現象，包括心跳快、血壓高、交感神經物質過度分泌等。同時這些病人的腦幹血管運動中樞有顯著發炎的情形，因此作者提出腸病毒71型致死的假說如下：腸病毒71型引起病人的腦幹發炎，繼而興奮了交感神經。而過量的交感神經物質如正腎上腺素的分泌，導致病童心臟衰竭而休克死亡。為了証實本假說，我們設計了五個實驗，包括兩個臨床研究、一個動物模式實驗、以及兩個離体細胞的實驗，而得到結論如下：腸病毒71型腦幹炎病人的肺水腫與心臟衰竭有關。心臟衰竭是致死的關鍵原因，其發生率是19%，死亡率高達77%。病人發生心臟衰竭前有心跳快、血壓高、交感神經物質過度分泌等交感神經過度興奮的現象。心臟病理顯示無心肌炎發現，但有凝固性心肌細胞溶解，心肌纖維變性以及心肌細胞凋亡的現象，這些變化是典型交感神經物質心肌毒性的病理變化。正腎上腺素心臟毒性的貓動物模式印証，其心臟超音波以及心臟病理變化與腸病毒71型腦幹炎病童的心臟衰竭表現非常相似。而離体細胞實驗也証實正腎上腺素會引起心血管細胞的凋亡，且其機轉與β-交感神經接受器、活性氧化物種、甲型腫瘤壞死因子、劊蛋白等訊息傳遞路徑有關。這些結果顯示腸病毒71型腦幹炎病童的心臟衰竭不是心肌炎所造成，而是腦幹血管運動中樞發炎導致交感神經物質過度分泌所導致的心臟毒性。積極治療此種心臟衰竭是挽救病人生命的關鍵，而β-交感神經阻斷劑、抗氧化劑、腫瘤壞死因子抗体、以及劊蛋白抑制劑等可能可以早期用來預防病人產生心臟衰竭。

The epidemic of enterovirus 71 infection causes the death of many children in Taiwan in 1998. The patients have three major complications including rhombencephalitis （brain-stem encephalitis）, pulmonary edema and heart failure. Because most of the patients has a normal heart size in chest radiogram and the heart specimen does not show the finding of myocarditis, most clinicians do not recognize the hear failure. Previous studies reported that the cause of death was pulmonary edema, which was neurogenic. Nevertheless, they did not clarify the role of heart. According to our meticulous observations of the patients, hypersympathetic activities including tachycardia, hypertension, and excessive release of the catecholamines precede the heart failure. We hypothesize that the pathogenesis of enterovirus 71 is as below: Enterovirus 71 infection causes rhombencephalitis, which activates the sympathetic nervous system. The overwhelming release of catecholamines results in the heart failure, causing shock and death. We conduct 5 experiments to prove this hypothesis, including 2 clinical studies, 1 animal model experiment, and 2 in-vitro cell experiments. The results showed that the pulmonary edema of enterovirus 71 rhombencephalitis is associated with heart failure. The heart failure is the critical cause of death and is complicated in 19% patients with enterovirus 71 rhombencephalitis. The mortality rate is 77%. Hypersympathetic activity including tachycardia, hypertension, and excessive release of catecholamines precedes the heart failure. Pathological examination does not show the findings of myocarditis, but reveals coagulative myocytolysis, myofibrillar degeneration and apoptosis of cardiomyocytes, which are the characteristics of catecholamine cardiotoxicity. Animal model of cats with norepinephrine cardiotoxicity shows the similar echocardiographic and pathological findings to those of patients with enterovirus 71 rhombencephalitis. In-vitro cell experiments show that norepinephrine is able to induce apoptosis in neonatal rat cardiomyocytes and endothelial cells through a β-adrenergic receptor-reactive oxygen species-tumor necrosis factor-caspase signaling pathway. The above findings prove that the heart failure in patients with enterovirus 71 rhombencephalitis is not caused by myocarditis but caused by catecholamines, which are released due to infection of vasomotor center. Early recognition and management of the heart failure are crucial to save patients’ lives. β-blockers, anti-oxidants, antibodies of tumor necrosis factor, and caspase inhibitors may be able to prevent the heart failure in patients with enterovirus rhombencephalitis.

中文摘要 6
英文摘要 8
中英文對照表 10
第一章 緒論 15
研究背景 16
假說 18
實驗設計 18
第二章 臨床研究（上） 19
腸病毒71型腦幹炎病童的肺水腫與左心室衰竭有關
引言 20
實驗方法 20
結果 23
討論 24
結論 26
圖表 27
第三章 臨床研究（下） 30
腸病毒71型腦幹炎的心臟併發症
引言 31
實驗方法 31
結果 34
討論 37
結論 41
圖表 42
第四章 動物模式實驗 47
正腎上腺素心臟毒性的貓與腸病毒71型
腦幹炎病童的心臟衰竭之比較
引言 48
實驗方法 48
結果 49
討論 51
結論 52
圖表 53
第五章 離体細胞實驗（上） 58
正腎上腺素引起大鼠心肌細胞凋亡是經由
活性氧化物種－甲型腫瘤壞死因子－劊蛋白
的訊息傳遞路徑
引言 59
實驗方法 60
結果 62
討論 65
結論 66
圖表 67
第六章 離体細胞實驗（下） 74
正腎上腺素引起大鼠內皮細胞凋亡是經由
降低Bcl-2以及活化β-交感神經接受器
和劊蛋白-2的訊息傳遞路徑
引言 75
實驗方法 76
結果 79
討論 80
結論 82
圖表 83
第七章 總結論 90
研究背景及假說 91
研究發現 92
治療啟示 93
參考文獻 94
相關研究發表 109

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