臺灣博碩士論文加值系統

近年來僅管抗生素能有效地抑制細菌生長，細菌性腦膜炎仍是一個高致死率的腦部發炎反應。其過程除了在腦脊髓液中含有大量的細胞激素及白血球外，也常伴隨著腦－血管屏障之損傷。我們以持續表現 b-galactosidase 的E. coli 突變種- M4 當作追蹤物，來探討細菌性腦膜炎所導致的腦－血管屏障損傷。我們發現在腦內給予E. coli 刺激後六小時，腦部開始有嗜中性球的浸潤。但腦－血管屏障之開啟，卻在腦內注射後一小時即可看見，且隨著時間之延長，腦－血管屏障開啟之情形也愈來愈明顯。根據細胞浸潤與否，將腦－血管屏障開啟分成兩階段：早期發生於腦內注射後一至五小時，此階段腦－血管屏障之變化主要由TNFa 及IL-1b 所導致；利用抗TNFa 及IL-1b 之抗體能將其抑制下來。晚期即是腦內注射後六至十二小時，主要是因為嗜中性球浸潤所造成。靜脈給予Vinblastine，將老鼠之嗜中性球去除掉，即會抑制晚期腦－血管屏障開啟。而整個發炎反應是一個連續的過程；以抗TNFa 及IL-1b 抗體處理老鼠不僅抑制早期，同時也抑制了晚期的腦-血管屏障開啟。另外，如果由腦內給予S. pneumoniae刺激，則整個腦-血管屏障開啟及細胞浸潤的時間會延至刺激後九至十二小時。由於腦-血管屏障開啟與細胞浸潤的時間一致，所以我們認為 S. pneumoniae 所引發的腦-血管屏障變化，主要由嗜中性球之浸潤所導致。周邊(靜脈或腹腔)給予E. coli及S. pneumoniae也會導致短暫的腦－血管屏障開啟;而開啟最明顯的時間分別為刺激後三小時及九小時，而這與敗血症發生時，血中 TNFa 濃度上升的時間吻合。如果給予抗 TNFa 抗體，則可抑制E. coli及S. pneumoniae導致的腦－血管屏障變化。另外，靜脈給予合成的 TNFa 也能造成腦－血管屏障開啟，而且開啟的程度與TNFa 濃度呈正相關。靜脈給予抗 TNFR1 抗體、亦或是在 TNFR2 基因剔除小鼠中，均發現靜脈給予 E. coli 所造成的腦-血管屏障開啟明顯的被抑制。由以上的結果發現敗血症發展過程中所產生的 TNFa 會透過 TNFR1 及 TNFR2受體的作用，造成腦-血管屏障通透性改變。除此之外，我們也發現 TNFa 會透過COX-2 的活化，進而造成腦-血管屏障通透性增加。腹腔給予COX-2之選擇性抑制劑-NS398 ，能有效地抑制腦內給予E. coli所造成的腦－血管屏障開啟，並且會加速腦部浸潤細胞進行凋亡。除此之外，自由基清除者-carboxyfullerenes能透過抑制細胞激素產生、嗜中性球浸潤、腦-血管屏障開啟的方式，抑制E. coli所引發之腦膜炎。

Despite the availability of effective antibiotic treatments, bacterial meningitis remains as an infection with a high mortality rate. The pathophsiology of bacterial meningitis involves increased production of cytokines and migration of leukocytes in brain, and followed by disruption of blood-brain barrier (BBB). Using a peripheral tracer with b-galactosidase activity, a simple method to quantify the degree of increased permeability of BBB during the development of bacterial meningitis was set up. A two-stage-alteration of BBB was found after intracerebral injection of E. coli. The early increase in BBB permeability occurred at 1-5 h post injection and was blocked by either anti-TNFa or anti-IL-1b antibodies. The late one, manifested at 6-12 h, was inflammatory neutrophil-associated and could be inhibited by Vinblastine pretreatment. Inhibition of the early E. coli-induced BBB opening blocked the development of the late one. Intracerebral injection of S. pneumoniae only induced one-stage-alteration of BBB and it was mediated by infiltrating neutrophils. Peripheral (intravenous or intraperitoneal) administration of E .coli and S. pneumoniae could induce the maximal increase of BBB permeabilty at 3 h and 12 h after injection, respectively. The timing is coincident with their kinetics of the circulating TNFa production in sepsis. Either E. coli or S. pneumoniae-induced increased permeability of BBB could be inhibited by anti-TNFa antibody. Intravenous injection of recombinant TNFa also induced the BBB opening. Furthermore, the E. coli-induced increase of BBB permeability could be inhibited by anti-TNFR1 antibody or was blocked in TNFR2 knockout mice. This indicated that the circulating TNFa generated in sepsis could induce the increase of BBB permeability through the TNF receptor. Moreover, TNFa could induce increased permeability of BBB through the activation of cyclooxygenase 2 (COX-2). The COX-2 inhibitor, NS398, inhibited not only the increase of BBB permeability, but also enhanced the apoptosis of the infiltrating neutrophils after E. coli-stimulation. Furthermore, E. coli-induced meningitis could be inhibited by carboxyfullerenes (a free radical scavenger, C60). C60 inhibited the cytokine production, neutrophil infiltration as well as the BBB opening.

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中文摘要
英文摘要
縮寫指引
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緒論
材料及方法
結果
總結
討論
參考文獻
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