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研究生:莊朝欽
研究生(外文):Chuang CC
論文名稱:探討人類單核球細胞上pH值調控蛋白及Indomethacin對細胞內鈣離子濃度與pH值的影響
論文名稱(外文):Effects of Indomethacin on Intracellular Ca2+, pH in the Human Monocyte
指導教授:羅時鴻羅時鴻引用關係
指導教授(外文):Loh SH
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
中文關鍵詞:人類單核球細胞
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前 言:
1). 鈣離子為細胞內之重要的訊息傳遞者,眾多文獻指出細胞內鈣離子 ([Ca2+]i ) 的恆定及調控與細胞內pH (pHi)值的變化有密切的關係,例如pHi大小會影響心臟細胞對[Ca2+]i相關反應的敏感性,但是在免疫細胞其相關的影響及確切機轉並未明瞭。
2). 就免疫細胞而言,在受到免疫性和化學性趨化因子的刺激活化後, 會快速生長分化,進而產生大量酸性代謝物,因此免疫細胞如何維持正常pHi便值得進一步研究;再者其 [Ca2+]i 的恆定及調控是否涉及酸鹼調控機轉需再深入研究。
3). Indomethacin是一種常被用於緩解類風濕性關節炎、僵直性脊柱…等炎症治療之non-steroidal anti- inflammatory drug (NSAID) , 根據目前許多研究報告指出,Indomethacin對於免疫細胞的增殖與分裂等功能具有直接性的抑制作用,因此indomethacin抑制免疫的作用,是否與 [Ca2+]i及pHi的改變有關,值得進一步探討。
實驗目的:
1). 測試螢光染劑Fura-2 AM (10 μM) 與BCECF AM (10 μM) 合併使用之可能性。
2). 研究monocyte之酸鹼調控相關的被動的緩衝能力 (buffering power;βi and βCO2) 及主動acid loading pH regulators。
3). 探討不同劑量之Indomethacin對於monocyte 之 [Ca2+]i 與pHi的影響。
4). 探討細胞外氫離子 (pHo) 對monocyte的 [Ca2+]i 與pHi之影響及關聯性。
5). 探討monocyte的 [Ca2+]i 與pHi調控之相關性。
實驗原理:
顯微螢光技術(microspectrofluorimetry technique)
利用對鈣離子與氫離子敏感的螢光指示染劑[Ca2+ :Fura-2 (10μM) ;H+:BCECF (10μM) ],分別透過不同之激發光波長激發[Ca2+:340 & 380 nm;H+:440 & 490 nm],於發散波長處510 nm 接收螢光強度比值R [Ca2+:(340/380);H+:(440/490)],比對校正曲線以表示[Ca2+]i與pHi的變化情形。
實驗方法:
1). 人類單核球的培養:人類單核球 (THP-1) 培養於培養液RPMI 1640中,內含10% fetal bovine serum (FBS) ,penicillin (100 U/ml) , streptomycin (100 mg/ml) , non- essential amino acid (100 mM) ,將其置於內含潮濕空氣,95% O2,5% CO2,37°C的培養箱中;每兩天更換一次培養液。
2). 人類單核球之 [Ca2+]i 與pHi的測定:取內含monocytes的培養液2 ml,以100 g離心10 分鐘,之後吸除上清液,加入HEPES buffer (pH 7.4,室溫),混合均勻。取細胞懸浮液100 μl,加入染劑Fura-2 AM (10 μM) and /or BCECF AM (10 μM)後避光靜置30分鐘。將loading螢光染劑的細胞,放入倒立式顯微鏡的灌流臺中,以顯微螢光技術進行實驗。
實驗結果 :
1). 螢光染劑Fura-2 (10 μM) 與BCECF-AM (10 μM) 在human monocyte之合併使用會互相干擾而改變螢光訊號及 [Ca2+]i 動態之變化。
2). Monocyte之 [Ca2+]I 的恆定及調控會受pHi的變化而影響。
3). Monocyte之被動緩衝能力呈現pHi依賴性 (於pHi 7.05~7.54) 且βCO2大於理論值的表現。
4). Human monocyte在pHi酸鹼調控上存在有兩個Cl- dependent的主動排鹼transporters,分別是CHE, AE。另外一個為K+ dependent的主動排鹼transporter -KHE。
5). Indomethacin降低monocyte之pHi (1μM ~1mM) 與 [Ca2+]i (300 μM, 1mM)調控之影響呈現一dose dependent 與time dependent的現象。
6). pHo (6.2~8.6)對monocyte 的[Ca2+]i與pHi之影響皆為一線性變化之關係。
7). (a) pHi影響monocyte之[Ca2+]i的恆定及調控之機轉是透過細胞膜上相關之的離子通道;(b) pHi的恆定及調控與 [Ca2+]o不相關。
結 論:
1). Human monocyte在pHi (7.05~7.54) 範圍區間之被動緩衝能力, β, 為pHi依賴性且βCO2 =10.527[pHi]2-110.06[pHi]+504.51,大於理論值βCO2=4.4938[pHi]2+11.723[pHi]+520.25。
2). Human monocyte存在有三個主動排鹼運輸蛋白,分別是CHE, AE,
KHE。
3). Indomethacin降低monocyte之pHi與 [Ca2+]i 之影響呈現一dose dependent 與time dependent的現象。

§ INTRODUCTION
Changes of intracellular pH (pHi) and intracellular Ca2+ ([Ca2+]i) have been implicated to affect many cellular functions. It is well established that two fundamental mechanisms, passive intracellular buffering power (β) and active transmembrane carriers, are responsible for pHi controlling in mammalian. However, the interrelationships between the cytosolic mechanisms controlling levels of Ca2+ and H+ are still poorly understand in the human monocytes (THP-1).
§ OBJECTS
The aims of the present study were using THP-1 to i) determine the underlying mechanisms for pHi regulation; ii) explore the interaction between the [Ca2+]i and pHi homeostasis; iii) test the effect of indomethacin on [Ca2+]i and pHi.
§ MATERIALS AND METHODS
1. Human monocyte (THP-1) was purchased commercially (Rockville, MA, USA) and cultured with RPMI 1640 medium.
2. In the whole study, pHi and [Ca2+]i change was measured by the technique of microspectrofluorimetry with the Ca2+ and H+-sensitive fluoroprobe, Fura-2 and BCECF, respectively.
§ RESULTS
In the study of β measuring, we found that CO2-dependent β(βco2) increase linearly as pHi rising, while the value of CO2-independent β( βi ) changes little. In the HEPES-buffered solution, pretreatment with DBDS (0.4 mM) and DIDS (0.4 mM), a specific Cl--OH- exchanger (CHE) and a Cl--HCO3- exchanger (AE) inhibitor, respectively, could inhibit 70 + 10% (N=6) pHi recovery slope following Na+-acetate (AH)-induced intracellular alkalosis. On the contrary, the pHi recovery following the AH-induced intracellular alkalosis was totally inhibited (N=8) by adding 150 mM [K+]o. Indomethacin dose dependently (1 μM ~ 1 mM) reduced pHi and [Ca2+]i. The intracellular alkalosis induced by AH caused a significant rise of [Ca2+]i (+110 +10 nM; N=12).
§ Conclusion
In the human monocytes,
1. The β is pHi-dependent (βi : y=10.875x2-120.42x+449.75; r2= 0.95; βco2 : y=10.527x2-110.06x+504.51; r2=0.94)
2. Three transmembrane transporters for acid loading,(i.e. CHE, AE, and KHE )have been characterized.
3. Indomethacin (1 μM ~1 mM) reduces pHi and [Ca2+]i dose- and time- dependently .

目 錄

目錄
圖目錄
中文摘要
英文摘要
第一章 緒論 5
第一節 人類單核球(monocyte)細胞在免疫上的角色及功能 5
第二節 人類單核球(monocyte)細胞的來源簡介 6
第三節 細胞內Ca2+濃度( [Ca2+]i)、pH (pHi)值與免疫細胞的活化、
增殖及凋亡的關係
第四節 [Ca2+]i對細胞功能的影響
第五節 [Ca2+]i恆定的調控
第六節 pHi的穩定對細胞功能的影響
第七節 細胞酸鹼調控的被動緩衝能力與主動運輸調控蛋白
第八節 [Ca2+]i 及pHi之相關性
第九節 細胞外pH值(pHo)改變,對[Ca2+]i 及pHi的影響
第十節 Indomethacin對於免疫發炎的影響
第十一節 Indomethacin對[Ca2+]i 及pHi的影響

第二章 實驗材料與方法
第一節 溶液與藥品
第二節 實 驗 原 理
第三節 顯微螢光技術 (microspectrofluorimetry technique)
第四節 實 驗 方 法
第五節 Sodium acetate (AH) pre-pulse technique
第六節 Ammonium chloride (NH4Cl) pre-pulse technique
第七節 統 計 方 法
第三章 實驗結果
第一節 Fura-2 AM與BCECF-AM合併使用的可能性
第二節 被動緩衝能力 (buffering power; βi and βCO2) 之探討
第三節 人類單核球細胞膜(THP-1)上之主動運輸排鹼蛋白
第四節 Indomethacin對[Ca2+]i,pHi的影響及可能機轉
第五節 pHo對[Ca2+]i 與pHi之影響及關聯性之探討
第六節 [Ca2+]i 與pHi調控之相關性探討
第四章 討論 63
第一節 Fura-2 AM與BCECF-AM無法合併使用偵測 [Ca2+]i 與pHi
第二節 THP-1被動緩衝能力 (buffering power; βi and βCO2)之探討
第三節 THP-1上的主動運輸排鹼蛋白
第四節 Indomethacin改變pHi的探討
第五節 Indomethacin造成細胞內酸化的機轉
第六節 Indomethacin 對[Ca2+]i的影響
第七節 pHo與pHi關係的探討
第八節 pHo與[Ca2+]i關係的探討
第九節 pHi 之變化與[Ca2+]i調控關係的探討
第十節 pHi之變化影響[Ca2+]i調控之機制
第五章 結論
第六章 參考文獻
圖 目 錄

(圖一) 顆粒性白血球的型態與功能
(圖二) 人類單核球的生成
(圖三) 細胞內鈣離子恆定調控之機制
(圖四) 平滑肌細胞的細胞內pH 調控蛋白
(圖五) indomethacin的化學結構特徵
(圖六) indomethacin的藥理機轉
(圖七) 顯微螢光測定法之裝置圖
(圖八) 螢光染劑BCECF激發光譜圖
(圖九) 螢光染劑Fura 2激發光譜圖
(圖十) 細胞載入螢光染劑BCECF or/and Fura 2
(圖十一) 細胞內pH值校正標準曲線
(圖十二) 弱酸-Sodium Acetate pre-pulse 技術
(圖十三) 弱鹼--NH4Cl pre-pulse 技術
(圖十四) 單一螢光染劑BCECF及合併使用Fura 2在Ratio F440/F490 螢光
訊號的影響
(圖十五) 單一螢光染劑Fura 2及合併使用BCECF在Ratio F340/F380 螢光
訊號的影響
(圖十六) 505與400 nm二分鏡波長對合併使用BCECF與Fura 2在Ratio

F440/F490、F340/F380螢光訊號的影響
(圖十七) 細胞內被動緩衝能力之測量及方法
(圖十八) 細胞內被動緩衝能力與pHi之關係曲線
(圖十九) 在HEPES緩衝溶液中,細胞外無Cl-環境對單核球細胞排鹼能
力的影響
(圖二十) 在HEPES緩衝溶液中,細胞外無Cl-及150 mM高鉀環境對單核
球細胞排鹼能力的影響
(圖二十一) 在HEPES緩衝溶液中,細胞外150 mM高鉀環境對單核球細胞
排鹼能力的影響
(圖二十二) 在HEPES緩衝溶液中,藥物DBDS對單核球細胞排鹼能力的
影響
(圖二十三) 在HEPES緩衝溶液中,藥物DBDS與DIDS對單核球細胞排鹼
能力的影響
(圖二十四) 在HEPES緩衝溶液中,藥物DBDS、DIDS與OMEPRAZOLE對單核
球細胞排鹼能力的影響
(圖二十五) 在HCO3-/CO2緩衝溶液中,細胞外無Cl-對單核球細胞排鹼能力
的影響
(圖二十六) 在HCO3-/CO2緩衝溶液中,藥物DBDS對單核球細胞排鹼能力的
影響
(圖二十七) 在HCO3-/CO緩衝溶液中,藥物DBDS與DIDS及合併使用150

mM高鉀環境對單核球細胞排鹼能力的影響
(圖二十八) 在HCO3-/CO2緩衝溶液中,細胞外150 mM高鉀環境對單核球細
胞排鹼能力的影響
(圖二十九)在HCO3-/CO2緩衝溶液中,藥物DBDS、DIDS與OMEPRAZOLE對單
核球細胞排鹼能力的影響
(圖三十) 在HEPES緩衝溶液中,不同劑量indomethacin對單核球細胞內
pH值的影響
(圖三十一) 在HEPES緩衝溶液中,不同劑量indomethacin對單核球排酸蛋
白NHE排酸能力的影響
(圖三十二) 在HEPES緩衝溶液中,不同劑量indomethacin對單核球排酸蛋
白NHE排酸能力抑制程度比較及劑量反應曲線的影響
(圖三十三) 在HEPES緩衝溶液中,1 mM劑量之indomethacin對於單核
球排酸蛋白NHE排酸作用的影響
(圖三十四) 在HEPES緩衝溶液中,不同劑量indomethacin對單核球細
胞內鈣離子濃度的影響
(圖三十五) 在HEPES緩衝溶液中,細胞外pH值與細胞內pH值之關係
(圖三十六) 在HEPES緩衝溶液中,細胞外pH值與細胞內鈣離子濃度之
關係
(圖三十七) 在HEPES緩衝溶液中,細胞內pH值影響細胞內鈣離子調控之
機制

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