臺灣博碩士論文加值系統

敗血症是急症與重症加護病人的死亡及長期加護病房醫療最重要的原因之一，也是社會醫療資源的重大負擔。敗血症候群的發生常伴隨著細菌性的感染，其中又以肺部疾患，如肺炎及成人呼吸窘迫症候群最常見，然而其病理機轉與治療至今仍未有突破。
已知花生四烯酸的代謝產物，包括前列腺素和白三烯素，是肺炎症反應與免疫的重要細胞介質，也是維持器官功能的必要物質。其缺乏或過多常伴隨肺炎與免疫疾病，包括肺間質纖維化，且是其致病機轉之一。
肺泡是肺部第一線的防禦細胞，也是花生四烯酸代謝產物的重要來源。已知在敗血症進行時，肺泡巨噬細胞的數目會有明顯的改變，並且肺泡巨噬細胞中類花生酸的釋放量會有顯著地減少，如白三烯素產量降低，但是其在敗血症肺傷害所可能伴演的角色，卻少有研究。
為了調查上述的情況，我們實驗是使用盲腸結紮及穿孔的手術，來導致敗血症的大白鼠模型。依實驗的需要，在盲腸手術後九小時或二十小時，取出其肺臟，利用支氣管肺泡灌流的技術來分離出肺泡巨噬細胞。經由十六小時的培養，肺泡巨噬細胞會標誌上氚-花生四烯酸。此時，再加入鈣離子通透劑刺激肺泡巨噬細胞，經由鈣離子通透劑的刺激會使得細胞釋出花生四烯酸的代謝產物。之後，使用反相高壓液相色層分析的技術來分析類花生酸代謝的情形，再利用放射性偵測器來偵測類花生酸的放射性活性。
因此，綜合本研究之結果，我們發現到在早期或晚期敗血症時，肺泡巨噬細胞花生四烯酸代謝產物的調節會有相異且不同程度的改變，因而造成肺防禦能力的不足，可能容易導致肺炎及成人呼吸窘迫症候群的發生。也就是說，我們的研究發現在敗血症早期及晚期時，肺泡巨噬細胞中的發炎介質白三烯素的產量降低，而前列腺素和血栓素的產生卻無顯著的影響。推測乃是敗血症早期和晚期會影響到肺泡巨噬細胞的功能，而使得五-脂氧合酵素代謝的能力受到抑制，並且伴隨著蛋白質表達的降低。
我們的研究將提供早期或晚期敗血症時，肺泡巨噬細胞中花生四烯酸代謝調節的改變，在敗血症伴隨肺傷害的致病機轉；也可能提供敗血症候群及其伴隨肺部傷害的不同治療方向。

Sepsis is frequently seen in hospitalized patients, especially in the ICU, and septic shock is one of the major causes of prolonged hospitalization and hospitalized deaths in Taiwan. Lung is almost always injured quite early in the septic processes. The manifestations of septic lung injuries are quite variable, which range from mild pneumonia to overwhelming lung edema, i.e., ARDS.
The mechanisms for lung injuries in septic patient are still unclear. To protect the lung from injury, many mediators are released by macrophages, including the AA metabolite PGs and LTs. These eicosanoids exert both pro-inflammatory and anti-inflammatory actions, and regulate many aspects of cell-mediated immunity.
AM, as the first-line defender of the lungs, synthesize significant amounts of these COX and 5-LO metabolites. During the processes of sepsis, AM and their releases of eicosanoids undergo changes in numbers and in quantity, respectively.
To investigate these problems, in this study, we used CLP male S-D rats as the model of sepsis. The amounts of 5-LO and COX metabolites released by AM from rats of 9 h and 20 h post-CLP operation, i.e., in early hyperdynamic and in late hypodynamic phases, respectively, were compared with those by AM from Sham-operated animals. In the experiments, AM were isolated by BAL and cultured in DMEM containing 10% FBS. During a 16-h incubation period, AM were labeled with [3H]AA, and thereafter, were stimulated with 1μM A23187. The released AA metabolites were extracted with a C18 cartridge and quantified by using HPLC with on-line radiodetection.
The results showed a decrease in 5-LO metabolic capacity and no significant changes in 15-LO, 12-LO and COX metabolic capacities in AM from septic rats of 9 hr and 20 hr post-CLP operation. The PLA2 capacity was not altered as well. These results indicated that the down-regulation of LT release by AM from septic animals might contribute to the pathogenic processes of septic lung injury. It is likely that the correction of AA metabolic alterations might be beneficial for the treatment of animals with septic lung injury. The results of immunoblot analysis showed that the steady state expression of 5-LO decreased in AM from septic rats of 9 hr and 20 hr post-CLP operation. The steady state expression of COX-1 and COX-2 were not altered in AM from septic rats.
In view of the effects of eicosanoids on cell inflammatory and immune responses, an understanding and application of the mechanisms governing the AM AA metabolism is presumably of profound importance in the treatment of sepsis and its complications.

誌 謝-------------------------------------------1
中文 摘要-------------------------------------------3
目 錄-------------------------------------------5
表 目 錄-------------------------------------------9
圖 目 錄-------------------------------------------11
符號與縮寫-------------------------------------------15
第一章 前言------------------------------------------19
壹、敗血症之概觀-------------------------------------19
一、敗血症的定義-------------------------------------19
二、敗血症的病原學-----------------------------------19
三、敗血症及其相關名詞-------------------------------20
四、敗血症的臨床表徵---------------------------------20
五、敗血症的病因及致病機轉---------------------------21
六、敗血症的病程-------------------------------------22
七、敗血症的病理生理學-------------------------------23
八、敗血症的治療及預防-------------------------------25
貳、類花生酸之概觀-----------------------------------26
一、類前列腺素的生物合成作用-------------------------26
二、磷脂酵素A2的命名及其分類-------------------------27
三、類前列腺素的臨床意義-----------------------------28
四、白三烯素的合成作用-------------------------------29
五、白三烯素的臨床意義-------------------------------30
參、肺泡巨噬細胞之概觀-------------------------------31
一、單核球吞噬細胞的衍化-----------------------------31
二、單核球吞噬細胞的命名-----------------------------32
三、單核球吞噬細胞的功能-----------------------------33
肆、研究之主題及設計---------------------------------33
第二章 材料與方法------------------------------------52
一、敗血症大白鼠的實驗模型---------------------------52
二、大白鼠巨噬細胞的分離及培養-----------------------54
三、大白鼠巨噬細胞的染色-----------------------------57
四、大白鼠巨噬細胞存活率的辨識-----------------------58
五、巨噬細胞標誌氚-花生四烯酸和用鈣離子通透劑刺激----59
六、細胞的放射性標誌物攝取量之分析法-----------------61
七、使用碳十八固相萃取的樣品處理匣萃取花生四烯酸的代謝
產物---------------------------------------------62
八、使用反相高壓液相色層分析法分析標準品-------------64
九、使用反相高壓液相色層分析法分析同位素-------------66
十、使用反相高壓液相色層分析法來分析類花生酸的外形---67
十一、由細胞的培養皿上萃取巨噬細胞-------------------68
十二、蛋白質定量分析法-------------------------------70
十三、十二烷基磺酸鈉聚丙烯醯銨凝膠電泳法-------------71
十四、西方點墨法-------------------------------------74
十五、免疫化學螢光增強偵測法-------------------------77
十六、資料及統計學的分析-----------------------------80
第三章 結果------------------------------------------81
一、支氣管肺泡灌流液體的回收率和肺泡巨噬細胞的數目---81
二、大白鼠肺泡巨噬細胞形態及存活率的辨識-------------82
三、肺泡巨噬細胞中內生性花生四烯酸代謝情形-----------83
四、正常及敗血症大白鼠的肺泡巨噬細胞中磷脂酵素A2產物的
釋放及代謝的能力---------------------------------85
五、正常及敗血症大白鼠的肺泡巨噬細胞中環氧合酵素產物的
釋放及代謝的能力-------------------------------- 86
六、正常及敗血症大白鼠的肺泡巨噬細胞中五-脂氧合酵素產物
的釋放及代謝的能力-------------------------------87
七、正常及敗血症大白鼠的肺泡巨噬細胞中十五-脂氧合酵素產
物的釋放及代謝的力-------------------------------89
八、正常及敗血症大白鼠的肺泡巨噬細胞中十二-脂氧合酵素產
物的釋放及代謝的力-------------------------------90
九、肺泡巨噬細胞中環氧合酵素-1蛋白質的表達情形-------91
十、肺泡巨噬細胞中環氧合酵素-2蛋白質的表達情形-------92
十一、肺泡巨噬細胞中五-脂氧合酵素蛋白質的表達情形----92
十二、肺泡巨噬細胞中肌動蛋白質的表達情形-------------93
第四章 討論------------------------------------------106
第五章 結論------------------------------------------113
第六章 參考文獻--------------------------------------115
英文 摘要-------------------------------------------128
作者 簡歷-------------------------------------------130
授 權 書-------------------------------------------131

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