臺灣博碩士論文加值系統

環境藥物濫用化學物引起生物體損害的能力稱為毒性，所產生的損害總稱為毒作用。毒性的大小可在一定的實驗條件下，利用動物實驗或其他方法檢測。毒物引起機體功能性或器質性改變後可引致相應的症狀。哺乳動物人類極易受到各種環境毒物（例如：中西醫學藥物濫用，甚或毒品濫用等）而改變自身生理病理機制進而對肝臟、腎臟、心臟、肺臟、胃腸等內臟組織器官造成傷害；藥品都有某種程度的毒性，倘若身體營養狀況不佳，許多藥品的毒性會變得更大，造成多方面的傷害。藥品會消耗體內的營養，增加營養素（鈣、鉀、維生素Ｂ群、Ｃ等）的排泄，擾亂正常消化與吸收能力等。許多人長期吃藥反而發生中樞神經細胞損傷、肝炎及腎炎等，不但未使原先病情獲得改善，反而導致嚴重的藥性毒害而引發系統細胞壞死的連鎖反應，造成肝硬化、肝功能衰竭、腎功能衰竭、尿毒症或惡化成腫瘤而死亡。本論文以兩大研究方向進行，第一研究方向：我們知道經由環境毒物所導致尿毒症之患者，對於洗腎醫療之需求頻繁，研究人員一直想要了解，是否該類血漿中重碳酸鹽濃度（PHCO3）較低的血液透析（HD）病人，其嗜中性白血球（Nutrophils）細胞內pH值（pHi）也相對偏低。相較於其他嗜中性白血球pHi正常或偏高者，此細胞內環境的酸化或許是促使吞噬作用（phagocytosis）增加的原因，然而此兩種現象之間的潛在細胞機制仍然不清楚。第二研究方向：對於海洛因、嗎啡濫用的懷孕母體，是否將導致其子代日後長期學習與記憶的認知功能病變；在基因調控表現機制是否受到影響。由於神經系統於人體實驗有其侷限性，因此本論文亦欲建立該主題之動物研究模式，以探討神經系統病變的機制。本實驗目的主要在研究分析母體嗎啡成癮對子代（P45）海馬迴CA1區（哺乳類動物的學習記憶功能的重要整合區）錐狀神經細胞中PSD-95與NMDA受體次單位（NR1，NR2A， NR2B）蛋白質和基因以及認知功能上的影響。實驗以大白鼠進行嗎啡成癮子代（P14，P45）一系列的研究。在本論文中，第一研究主題結果顯示：在過去的研究中顯示，我們發現血漿中重碳酸鹽（HCO3-）濃度較低時，嗜中性白血球pHi值明顯偏低，另外還有細胞凋亡延遲、吞噬作用和氧爆作用增加等情況。這些改變在矯正A組代謝性酸中毒一個月之後減少。體外實驗亦證明嗜中性白血球的pHi與細胞凋亡呈現正相關，而與吞噬作用、氧爆作用則呈現負相關。綜合實驗結果顯示：血液透析病人酸鹼值及重碳酸鹽較低，其嗜中性白血球細胞內酸鹼值（pHi）也偏低；而細胞內酸化可能是導致細胞凋亡延遲、吞噬作用和氧爆作用增加的原因。第二研究主題結果顯示： 從即時聚合酶連鎖反應法的結果，母體嗎啡成癮會導致子代（P14，P45）PSD-95和NMDA受體次單位（NR1，NR2A，NR2B）mRNA表現顯著的減少，而以immunoblotting分析PSD-95和NMDA受體次單位（NR1， NR2A，NR2B）蛋白質表現也顯示出顯著減少的相同結果。此外，以coimmunoprecipitation分析子代（P14，P45）PSD-95和NMDA受體次單位突觸複合體間之蛋白質交互作用的情形，結果顯示相較於正常組有顯著下降趨勢。而從八臂放射迷宮此項行為學分析結果顯示，其認知功能明顯比正常組來的差。這研究結果將對於嗎啡成癮對子代神經行為認知功能的改變，以及發育中大腦PSD-95與NMDA受體次單位蛋白質間之交互作用的機制改變有更進一步的了解。

本文目錄
圖表目錄
中文摘要
英文摘要
第一章 緒論
第一節 人類和環境的關係
第二節 環境毒素與腎臟尿毒症之致病機制
第三節 環境毒物藥物濫用與神經細胞損傷之致病機制
第四節 本論文之研究目的與策略
第二章 材料與方法
第一研究主題實驗對象與方法
1. 生物體內實驗設計
2. 生物體外實驗設計
3. 病患選擇
4. 血液透析
5. 生化分析
6. 分離與準備嗜中性白血球
7. 測量細胞內pH值
8. 嗜中性白血球吞噬作用
9. 分析HD病人與正常控制組的CD11b、CD18、CD14及TLR-2、TLR-4的表現量
10. 以流式細胞儀鑑定嗜中性白血球的存活、凋亡和壞死（necrosis）情形
11. DNA片段化分析
12. 測量Caspase-3的活性
13. 氧爆作用-超氧化物（superoxide；SO）分析
14. 過氧化氫（hydrogen peroxide）分析
15. 統計分析
第二研究主題實驗對象與方法
1. 實驗動物處理
2. 海馬迴腦切片製備
3. 即時聚合酶連鎖反應（Real- time polymerase chain reaction）
4. 免疫共同沈澱法（Co-immunoprecipitation）和西方墨點分析法（western blot analysis）
5. 八臂放射迷宫（8-arm maze）測試法
6. 統計分析
第三章 實驗結果
研究主題一
1.尿毒患者和健康個體的嗜中性白血球CD11b、CD18、CD14、TLR-2和TLR-4表現量
2. pHi對尿毒症患者的嗜中性白血球CD11、CD18、CD14和TLR-2、TLR-4表現量的影響
3. 尿毒症病患A、B、C和A+組和健康個體的嗜中性白血球吞噬作用
4. 尿毒症病患和健康個體的嗜中性白血球細胞凋亡作用
5. 尿毒症病患和健康個體的嗜中性白血球吞噬作用
6. 尿毒症病患和健康個體由噬中性白血球所媒介的氧爆反應
7. pHi對尿毒症患者的嗜中性白血球細胞凋亡與吞噬作用的影響
8. pHi對尿毒症患者的嗜中性白血球氧爆反應的影響
研究主題二
1. 生長發育的特徵
2. 八臂放射迷宮測試的結果
3. NMDAR and PSD-95在mRNA的相關表現
4. NMDA受體與PSD-95的蛋白質表現量
5. NMDA受體與PSD-95形成突觸複合體的組合
第四章 討論
研究主題一
1. 尿毒症患者之嗜中性白血球的pHi與細胞凋亡
2. 嗜中性白血球的pHi、吞噬作用和氧爆作用
3. 代謝性酸中毒與尿毒症病患嗜中性白血球功能的關聯
研究主題二
1. 嗎啡海洛英成癮母體對子代在長期神經功能的影響
2. 嗎啡成癮母體對子代在海馬迴CA1區錐狀神經細胞中NMDA受體次單位與PSD-95複合體的影響
第五章 結論
第六章 附圖
第七章 參考文獻

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