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系統識別號 U0026-0812200912113816
論文名稱(中文) 第一型血基質氧化酵素在Dextromethorphan降低肝臟傷害與膽結石生成中扮演之角色
論文名稱(英文) Dextromethorphan Protects Against Liver Damage and Gallstone Formation:Role of Heme Oxygenase-1
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 94
學期 2
出版年 95
研究生(中文) 劉郁孚
研究生(英文) Yu-Fu Liu
學號 t3693402
學位類別 碩士
語文別 英文
論文頁數 78頁
口試委員 口試委員-余俊強
口試委員-周楠華
指導教授-謝淑珠
口試委員-陳炯瑜
中文關鍵字 第一型血基質氧化酵素  膽結石 
英文關鍵字 gallstone  heme oxygenase-1 
學科別分類
中文摘要 膽結石被認為是一種與氧化壓力有關的疾病,過去的研究指出,給予抗氧化劑可以有效的預防天竺鼠體內膽結石的生成。在結石生成的初期,發炎反應也扮演著相當重要的角色。第一型血基質氧化酵素 (Heme oxygenase-1, HO-1) 是細胞分解代謝血基質的速率決定步驟酵素;有許多研究指出HO-1具有抗氧化、抗發炎及抗細胞凋亡的能力,提供細胞防禦及保護的機制。過去已有研究指出,在鐮刀型貧血的動物模式中,HO-1可經由抑制發炎反應,有效減緩因缺氧/再灌注所引起的血管阻塞。Dextromethorphan (DM) 是目前被廣泛使用的止咳劑;然而近年來有研究指出,DM可經由抑制氧化壓力及發炎反應來避免腦部及肝臟受到由內毒素所引起的傷害,而達到保護的效果。因此本研究利用Huh-7人類肝癌細胞株,探討DM在體外對於肝細胞表現HO-1之影響;並利用天竺鼠膽管部份結紮致成色素膽結石的動物模式,探討DM是否經由HO-1的誘發而對膽結石的生成及肝臟損傷達到保護的作用。在細胞培養系統中,DM可有效誘發Huh-7細胞株表現HO-1 mRNA及蛋白質。而在動物模式中,於天竺鼠膽管結紮前一天開始,每日給予腹腔注射DM,分別於膽管結紮後六小時、一天、七天、及十四天,觀察其膽泥/膽結石生成情形以及病理組織切片染色,並測定血清中AST、ALT、GGT活性及膽紅素以評估DM對於膽結石致成及肝臟損傷所造成之影響。為了更進一步探討作用的機轉,測定膽汁中的氧化壓力與色素成分及肝臟細胞凋亡的情形。此外,也測定肝臟HO-1 mRNA表現與HO的活性來評估HO-1所扮演之角色,以及肝臟TNF-α mRNA表現。結果顯示DM的確有效地降低由膽管結紮所致成之膽泥/膽結石生成。而由AST、ALT、GGT及組織切片染色的結果顯示,DM的給予使得膽管結紮後六小時明顯降低肝臟TNF-α mRNA表現,並在結紮後一天明顯上升膽汁總抗氧化能力及降低MDA,而減緩肝臟所受到的傷害。但是DM的給予對於肝臟細胞凋亡的影響並不顯著。這些結果顯示DM對肝細胞所提供的保護主要發生在膽管結紮的初期,而且可能是經由抗發炎及抗氧化來提供保護的能力。在膽管結紮後一天,HO-1 mRNA可經由DM的給予而被顯著誘發,顯示HO-1在DM所提供的保護機制中具有其重要性。此外,DM於膽管結紮後六小時即可顯著抑制TNF-α mRNA表現。總結來說,DM可能經由抑制發炎反應及氧化壓力來對膽結石生成及肝臟損傷提供保護作用,而HO-1參與在此機轉中。


英文摘要 Gallstone formation is considered as an oxidative stress-associated disease. It has been proved that administration of antioxidants effectively reduced gallstone formation in guinea pigs. In the initiation of the disease progression, inflammation also plays an important role. Heme oxygenase-1 (HO-1), an inducible isoform, is the rate limiting enzyme of heme degradation. HO-1 is thought to play an important role in antioxidative, anti-inflammatory, and antiapoptotic defense mechanisms. Recent studies indicate that vaso-occlusion caused by hypoxia / reoxygenation in transgenic sickle mice was significantly reduced by HO-1 induction through the inhibition of inflammation. Dextromethorphan (DM) is one of the most widely used over-the-counter antitussives for the treatment of cough associated with acute upper respiratory tract infection. However, through the inhibition of oxidative stress and inflammation, DM was shown to protect against LPS-induced neurodegeneration and liver damage. The aim of the study is to investigate whether DM would ameliorate liver damage and gallstone formation through the induction of HO-1 in vitro and in vivo. Incomplete common bile duct ligation (BDL) was performed in male guinea pigs to induce gallstone formation and liver damage. DM was intra-peritoneally administered daily starting from one day prior to surgery. At 6-hour, 1-, 7-, and 14-day of BDL, sludge/stone formation in gallbladder, serum liver function profile, and liver histology were examined to evaluate the effects of DM on gallstone formation and liver damage. To further investigate the mechanism of DM’s effects, bile pigments and oxidative stress indicators, total antioxidant activity (TAA) and malondialdehyde (MDA), were determined in bile. Caspase 3 activity, TNF-α mRNA expression, HO-1 mRNA expression, and HO activity in liver homogenates were determined. The results showed that HO-1 was induced by DM in vitro. For the in vivo system, DM effectively reduced sludge/stone development. Significant decrease of serum AST, ALT and GGT, and liver HAI score was found at 6 hour of ligation with DM treatment. In addition, the DM treatment increased TAA and decreased MDA in bile at 1-day ligation. However, caspase 3 activities in liver homogenates did not change significantly after DM treatment. These results indicate the protection role of DM in the early stage of gallstone formation, and may be through the mechanism of anti-inflammation and anti-oxidative stress. DM significantly induced liver HO-1 mRNA expression at 1-day ligation, suggesting the involvement of HO-1 in the protective effects of DM. At 6-hr of ligation, DM effectively inhibited TNF-α mRNA expression. In conclusion, administration of DM protects against gallstone formation and liver damage caused by bile duct ligation. DM may provide the protection through the induction of HO-1, associated with anti-inflammation and antioxidative stress

論文目次 Contents
Abstract (in Chinese)……………………………………………………………I
Abstract (in English)……………………………………………………………II
Acknowledgments……………………………………………………………………IV
Contents……………………………………………………………………………V
Table List…………………………………………………………………………VII
Figure List…………………………………………………………………………VIII
Appendix List………………………………………………………………………IX
Introduction………………………………………………………………………1
Anatomy of the Biliary System…………………………………………………1
Bile Secretion and Functions…………………………………………………1
Gallstones…………………………………………………………………………2
Pathogenesis of Pigment Gallstones…………………………………………3
Animal model of Pigment Gallstone……………………………………………4
Management of Gallstone Disease………………………………………………4
Oxidative Stress and Gallstone Disease……………………………………5
Oxidative Stress and Biliary Obstruction…………………………………6
Antioxidants in Gallstone Disease and Liver Injury……………………7
Heme Oxygenase……………………………………………………………………7
Induction and Regulation of HO-1……………………………………………9
HO-1 and Antioxidation…………………………………………………………10
HO-1 and Antiapoptosis…………………………………………………………11
HO-1 and Anti-inflammation……………………………………………………12
HO-1 in Disease Model……………………………………………………………13
Dextromethorphan…………………………………………………………………13
Aims and Strategies………………………………………………………………15
Materials and Methods……………………………………………………………16
1.Experimental animals…………………………………………………………16
2.Analysis of sludge and gallstones…………………………………………17
3.Analysis of liver histology by Hematoxylin-Eosin staining…………17
4.Serum biochemical analysis…………………………………………………17
5.Determination of liver HO-1 mRNA by real-time PCR……………………18
6.Preparation of GP liver cytosols / microsomes…………………………21
7.Liver total protein analysis………………………………………………22
8.Determination of liver HO enzyme activity………………………………22
9.Determination of liver caspase 3 activity………………………………24
10.Determination of biliary total antioxidant activity (TAA)………25
11.Determination of biliary malondialdehyde (MDA) by HPLC……………26
12.Analysis of bile pigment by HPLC…………………………………………26
13.Cell culture……………………………………………………………………27
14.Determination of Huh-7 HO-1 mRNA by real-time PCR…………………28
15.Determination of Huh-7 HO-1 protein expression by western blot…28
16.Statistical Analysis…………………………………………………………30
Results………………………………………………………………………………31
Discussion…………………………………………………………………………37
Conclusion…………………………………………………………………………45
References…………………………………………………………………………46
Tables………………………………………………………………………………56
Figures………………………………………………………………………………57
Appendixes…………………………………………………………………………74
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