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研究生:董全緯
研究生(外文):Chuan-Wei Dong
論文名稱:探討大鼠腦缺血後炎症細胞的浸潤
論文名稱(外文):Characterization of Inflammatory cells Infiltration in Ischemic Rats
指導教授:黃勇三
指導教授(外文):Yong-San Huang
學位類別:碩士
校院名稱:國立中興大學
系所名稱:獸醫學系暨研究所
學門:獸醫學門
學類:獸醫學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:中文
論文頁數:69
中文關鍵詞:腦缺血單核球/吞噬細胞CD45/CD11b免疫抑制
外文關鍵詞:transient cerebral ischemiamicroglia/macrophagesCD45/CD11bimmunosuppression
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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.
目次 ……………………………………………………………………………i
圖表目次 ………………………iii
第一章 緒論 …………………………………………………………………1
第二章 文獻探討 ……………………………………………………………2
第一節 腦缺血介紹 ……………………………………………………2
第二節 腦缺血之病理變化 ……………………………………………4
第三節 腦缺血與血腦障壁的關係 ………………………………………9
第四節 腦缺血後的炎症反應 …………………………………………11
第五節 腦缺血與免疫抑制的關係 ……………………………………14
第六節 腦缺血實驗動物模式 …………………………………………15
第三章 實驗目的 ……………………………………………………17
第四章 實驗材料與方法 ……………………………………………………18
一、試藥 ………………………………………………………………19
二、實驗動物 ………………………………………………………19
三、腦缺血再灌流動物模型 ……………………………………………19
四、動物行為評估 ……………………………………………………19
五、白血球總數 ……………………………………………………19
六、白血球分類 ……………………………………………………20
七、組織處理 ……………………………………………………20
八、梗塞區域評估 ……………………………………………………20
九、組織病理學染色 ……………………………………………………21
十、免疫螢光染色 ……………………………………………………21
十一、蛋白質備製 ……………………………………………………22
十二、西方墨點法 (Western blot) ……………………………22
十三、酵素連結免疫分析法 (ELISA) ………………………………………23
十四、酶譜法 (Zymography) ………………………………………………24
十五、腦組織中炎症細胞分離 ……………………………………………24
十六、血液中白血球分離 …………………………………………………25
十七、分離脾臟及胸腺中白血球 …………………………………………25
十八、流式細胞儀分析 ……………………………………………………25
十九、分析方法26
第五章 實驗結果 27
一、腦缺血再灌流手術前後體重變化 ……………………………27
二、中風梗塞區域評估 ………………………………………………27
三、腦缺血後行為變化評估 …………………………………………27
四、腦部組織病理學變化 ……………………………………………28
五、免疫螢光染色 ……………………………………………………29
六、周邊血液免疫細胞變化 …………………………………………29
七、腦部組織中發炎介質偵測 ………………………………………30
八、腦組織中微神經膠細胞活化分析 ………………………………31
九、腦缺血後脾臟及胸腺的重量變化 ………………………………32
十、脾臟及胸腺中免疫淋巴細胞變化 ………………………………32
十一、周邊血液中免疫細胞分類 ………………………………………33
第六章 結論 ………………………………………………………………34
第七章 討論 …………………………………………………………………35
第八章 參考文獻 62


圖表目次
圖4-1 大鼠體重在腦缺血後各個時間點的百分比變化 …………………40
圖4-2 腦缺血梗塞面積評估 ………………………………………………41
圖4-3 腦缺血前後行為變化 ………………………………………………44
圖4-4 腦部缺血後皮質部及紋狀體組織病理學變化 ……………………45
圖4-5 免疫螢光染色偵測腦缺後皮質部巨噬細胞分佈 …………………46
圖4-6 血液中白血球總數及白血球分類 …………………………………49
圖4-7 血液中分類白球總數 ……………………………………………49
圖4-8 Interleukin-1β在腦缺血損傷側及腦缺血對側的變化 …………50
圖4-9 腦缺血後MMP在腦缺血損傷側及腦缺血對側的變化 …………52
圖4-10 COX-2在腦缺血損傷側及腦缺血對側的變化 …………………53
圖4-11 腦組織中炎症細胞CD45-PE/CD11b-FITC之螢光表現 …………54
圖4-12 CD45+/CD11b+細胞群中CD45+表現的細胞群數量分析 ………55
圖4-13 為CD45+/CD11b+細胞群中CD45+表現的細胞群數量量化分析…56
圖 4-14 為CD45+/CD11b+細胞群中CD45+表現的細胞群數量經量化分析後,腦缺血損傷區域與腦缺血對側區域的比較……………………58
圖4-15 大鼠脾臟及胸腺的重量變化………………………………………59
圖4-16 大鼠脾臟及胸腺中淋巴細胞分佈…………………………………60
圖4-17 血液中免疫細胞細胞分佈…………………………………………61
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