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系統識別號 U0026-2508201011341100
論文名稱(中文) 一氧化碳在促進膽汁分泌和膽汁淤積的角色
論文名稱(英文) The role of carbon monoxide in choleresis and cholestasis
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 高琪雅
研究生(英文) Chi-Ya Kao
學號 t3697401
學位類別 碩士
語文別 英文
論文頁數 75頁
口試委員 指導教授-謝淑珠
口試委員-陳炯瑜
口試委員-吳誠中
口試委員-余俊強
口試委員-蔡曜聲
中文關鍵字 一氧化碳  膽汁 
英文關鍵字 Carbon monoxide  bile 
學科別分類
中文摘要 膽汁淤積是由於膽汁無法順利從肝臟分泌,運送到小腸利用所造成的。長期的膽汁淤積使得帶有毒性的膽鹽堆積在肝臟細胞,因而導致肝臟受損。在肝臟或膽道細胞中,總膽酸(total bile acid)、總麩胺基硫(total glutathione; GSH)、以及重碳酸鹽(bicarbonate)的分泌,帶動滲透壓進而促進膽汁的分泌。一些研究指出,一氧化碳具有調控膽汁分泌的效果。然而,究竟一氧化碳的角色是促進或是抑制膽汁的分泌,仍具爭議性。本篇研究旨在探討一氧化碳對膽汁淤積的調控以及其作用的機制為何。本篇實驗的動物模式是利用Sprague–Dawley大鼠,插管PE-10至總膽管,以每小時收集膽汁一次。Dicholomethane (DCM)則是本篇研究所使用的一氧化碳前驅藥物,我們利用給予大鼠DCM來研究一氧化碳對膽汁形成的影響。為了更進一步探討一氧化碳作用的機制,我們分析了實驗動物的膽汁pH值、重碳酸鹽、總膽酸、麩胺基硫、以及一氧化氮的濃度。實驗結果發現,給予DCM四小時後,血液中一氧化碳血紅素(carboxyhemoglobin; COHb)含量顯著升高,而膽汁分泌量以及total GSH的濃度分別增加了1.6倍和2.1倍。此外,相較於GSH,一氧化碳所造成的膽汁分泌增加伴隨的是膽汁中glutathione disulfide (GSSG) 濃度的增加(倍數之變化,DCM 和對照組: 0.71 ± 0.16 vs. 0.35 ± 0.05, p<0.05)。然而,在給予DCM之後,膽汁中重碳酸鹽和總膽酸的濃度皆沒有顯著的變化。給予DCM四小時之後,大鼠血清中硝酸鹽(nitrate)和亞硝酸鹽(nitrite)的含量相較於對照組有顯著的增加(224.0 ± 17.1 μmol/L vs. 165.6 ± 19.8 μmol/L, p<0.05)。另外,肝臟中誘發型一氧化氮合成酶(inducible nitric oxide synthase)的蛋白質表現在給予DCM的組別中相較於對照組亦有顯著上升(p<0.05)。給予DCM亦增加了肝臟細胞膜上運輸蛋白Mrp2之表現(DCM和對照組: 0.30 ± 0.04 vs. 0.15 ± 0.01, p<0.01)。給予一氧化氮合成酶之抑制劑Nω-nitro-L-arginine methyl ester (L-NAME)消除了一氧化碳所引發之膽汁形成以及膽汁GSSG的分泌效果,然而對於膽汁GSH的分泌則沒有顯著影響。在利用雌激素誘發膽汁淤積的模式當中,一氧化碳的給予,透過增加total GSH以及總膽酸的分泌達到了改善膽汁分泌的效果,也進而降低了血清中鹼性磷酸酶、總膽酸以及總膽紅素的含量。總結來說,本研究結果顯示一氧化碳能夠藉由增加誘導型一氧化氮合成酶以及運輸蛋白Mrp2之表現,促進膽汁GSSG的分泌以達到增加膽汁形成的效果。一氧化碳所促進的膽汁分泌增加能應用於防護雌激素所造成的膽汁淤積。
英文摘要 Cholestasis is a condition caused by an impairment of bile excretion from liver into the small intestine. Prolonged cholestasis results in liver injury by accumulating toxic bile salts in hepatocytes. Bile excretion is an osmotic process driven by secretion of bile acids, total glutathione, and bicarbonate in hepatocytes and cholangiocytes. Carbon monoxide (CO), product of heme oxygenase, has been shown to exert physiological roles in biliary excretion. However, whether CO stimulates or suppresses bile formation remains controversial. This study was aimed to investigate the effects of CO on bile output and its underlying mechanism. The common bile ducts of Sprague-Dawley rats were cannulated with a polyethylene P-10 tube to collect bile hourly. Dichloromethane (DCM) was used as a CO pro-drug. The effect of CO on bile formation was examined. To further investigate the mechanism of CO effect, biliary pH, concentrations of bicarbonate, total bile acids, total glutathione (GSH) and nitric oxide were determined. A significant increase of carboxyhemoglobin (COHb) was observed at the fourth hour after DCM administration. Basal bile output and biliary total GSH concentration were increased 1.6 fold and 2.1 fold, respectively, at the fourth hour after DCM administration. Furthermore, CO-induced increase in bile output was associated with a concomitant increase of biliary glutathione disulfide (GSSG) (fold change in DCM vs. control: 0.71 ± 0.16 vs. 0.35 ± 0.05, p<0.05) instead of GSH. However, no significant change of bicarbonate and total bile acids concentration in bile was identified after DCM administration. At the fourth hour after DCM administration, the rats had significantly higher serum nitrate and nitrite levels, compared to control (224.0 ± 17.1 μmol/L vs. 165.6 ± 19.8 μmol/L, p<0.05). In addition, the expression of hepatic inducible nitric oxide synthase (iNOS) was significantly higher in DCM group than that in control group (p<0.05). DCM administration further increased the expression of hepatic Mrp2 (DCM vs. control: 0.30 ± 0.04 vs. 0.15 ± 0.01, p<0.01). The administration of Nω-nitro-L-arginine methyl ester (L-NAME), inhibitor of NOS, abolished CO-induced bile formation and biliary GSSG excretion, while biliary GSH remain unchanged. In the animal model of estrogen-induced cholestasis, CO supplement improved bile output through stimulating total GSH and total bile acid excretions, and decreased serum levels of ALP, total bile acid, and total bilirubin. In conclusion, CO increased biliary GSSG excretion by inducing iNOS and Mrp2 expressions and resulted in choleresis. CO-induced choleresis may play a role in protecting against estrogen-induced cholestasis.
論文目次 Abstract (in Chinese)........I
Abstract (in English)........III
Acknowledgment......V
Index........VI
Table list........VIII
Figure list........IX
Appendix list........X
Introduction........1
Bile formation and bile acid transporters........1
Regulation of GSH synthesis........2
Regulation of bile acid synthesis........3
Hepatocellular cholestasis........4
Cholestasis induced hepatocyte apoptosis........5
Physiological effects of carbon monoxide........6
Cross talk between CO and nitric oxide........7
Effects of CO on bile formation........8
Protection of CO against liver injury........9
Dichloromethane – pro-drug of CO........10
Aims and strategies........12
Materials and methods........13
Animal experiments........13
Bile analysis........15
Blood analysis........20
Total protein analysis........22
Malondialdehyde in liver homogenates........23
Protein expression by western blot analysis........25
Statistical analysis........28
Results.......29
Discussion........35
Conclusion........39
References........40
Tables........54
Figures........56
Appendixes........67
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