Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/13581
標題: 探討大鼠腦缺血後炎症細胞的浸潤
Characterization of Inflammatory cells Infiltration in Ischemic Rats
作者: 董全緯
Dong, Chuan-Wei
關鍵字: transient cerebral ischemia;腦缺血;microglia/macrophages;CD45/CD11b;immunosuppression;單核球/吞噬細胞;CD45/CD11b;免疫抑制
出版社: 獸醫學系暨研究所
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摘要: 
局部腦缺血會因為腦部缺乏氧氣及血流的供應而引發一連串的病理變化。缺血後神經組織並不會在第一時間出現變性或死亡,而是以漸進性的刺激造成腦部大規模的傷害並導致嚴重的組織損傷。造成腦缺血後遲發性神經細胞死亡,以炎症細胞浸潤為主要原因,浸潤的炎症細胞包括腦缺血急性期的嗜中性白血球以及中晚期周邊血液中單核球/吞噬細胞。近年來的研究認為,早期因損傷而活化的微神經膠細胞及周邊血液浸潤的吞噬細胞會釋放大量的細胞激素、化學趨化素等發炎介質,為腦缺血後組織持續性傷害的主要原因。臨床上,腦中風除了造成嚴重致死外,大多有後遺症的發生。包括體重減輕、活動力衰退、四肢不協調等神經症狀以及影響周邊的免疫系統,造成免疫抑制併發細菌感染,提高中風後的致死率。然而,中樞神經損傷造成周邊免疫系統的機制尚未明瞭,大多推測與周邊免疫系統中調節T細胞的活化而使免疫細胞凋亡或是交感神經過度興奮並造成脾臟及胸腺萎縮的機制有關。
為了瞭解腦缺血後腦部炎症細胞浸潤及免疫抑制的機轉。本論文利用腦缺血再灌流手術誘發大鼠腦缺血性梗塞的神經傷害動物模式,觀察腦缺血後神經損傷後動物的體重、行為變化,分析梗塞區域面積、組織病理、血液中白血球以及細胞激素的變化,特別著重於探討腦缺血後,腦部微神經膠細胞活化及周邊血液中巨噬細胞浸潤的情形。最後,本論文更嘗試透過分析脾臟及胸腺免疫細胞的變化來探討大鼠在腦缺血後是否出現免疫抑制現象。
實驗結果發現,腦缺血後的大鼠體重明顯減輕、活動力降低,發炎相關因子如IL-1β、MMP、及COX-2等的表現增加。組織病理檢測觀察到神經細胞變性及大量吞噬細胞的浸潤。流式細胞儀分析發現,腦缺血初期的第1天是以微神經膠細胞 (CD45+high/CD11b+high) 活化為主,第5天後則逐漸被血液來源的吞噬細胞 (CD45+med/CD11b+high) 所取代。脾臟及胸腺明顯萎縮及細胞組成改變,但是調節T淋巴細胞 (CD4+/Foxp3+-Treg) 數量則無顯著變化。
本實驗是以大鼠進行中大腦動脈缺血再灌流手術的動物模式,探討大鼠腦缺血後的病理機轉,並建立完整的大鼠腦缺血模型分析方式以便未來能藉由此分析模式尋找抑制病變途徑的方法或藥物,進而改善目前臨床上治療腦中風的方法及藥物並降低中風的後遺症。

The principal pathophysiological changes in transient cerebral ischemia are energy failure, ionic and neurotransmitter disturbance, acidosis, excitotoxicity, inflammatory cells infiltration, vascular permeability change, oxidative stress, and programmed cell death. Evidence shows that the delayed neuronal death is attributed to over-activated inflammatory responses including inflammatory cell recruitment, activation, and subsequent production of cytotoxic mediators such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Among the recruited inflammatory cells, resident microglia with an amoeboid macrophage phenotype are activated within the injured areas at the early phase and macrophage migrate from peripheral circulation toward the lesion site at the late phase. Since microglia and marcophage play critical roles in the induction and progression of inflammatory reaction, the present study was aimed to elicit their dynamic changes and potential involvement in post-ischemic brain injury in a stroke animal model.
Using focal cerebral ischemia/reperfusion animals, several pathophysiological changes were temporally and spatially detected and analyzed, including neurobehavior, infarction size, histopathology, neuron degeneration, and inflammatory cytokines. In addition, the apparent recruitment of microglia/macrophages as well as resting-to-activated switch were detected in ischemic cortical tissues. For the assessment of immunosuppression, we had focused on both early and late events in the peripheral immune system, sush as leucocytes change in blood, spleen and thymus during ischemia of rat.
Our experimental results showed that post-ischemic brain injury was accompanied by weight loss and hypoactivity. Inflammatory factors sush as IL1-β, MMPs, and COX-2 were over-expressed in the injury side. Over-activated microglia (CD45+high/CD11b+high) was observed in the first day and macrophage from peripheral circulation (CD45+med/CD11b+high) was observed in the 5 days after ischemia. The tissue weight of both of spleen and thymus were decreased after ischemia. Because of no obviously change in Treg cells (CD4+/Foxp3+-Treg) in spleen and thymus, there was no evidence indicated the association of immunosuppression and organ atrophy after stroke.
Our research was focusing on the development of the experimental focal cerebral ischemia model and evaluation of pathophysiology changes after ischemia. Through the application of these assayed platform and identified critical target molecules, it will help to screen and evaluate poteintially neuroprotective compounds and develop therapeutic strategies for the prevention and treatment of stroke.
URI: http://hdl.handle.net/11455/13581
其他識別: U0005-1808200816041900
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