第一型血色素氧化酵素（Heme oxygenase 1, HO-1）是一種具細胞保護作用的蛋白質，經由降低細胞氧化壓力和調節多種細胞作用像是細胞激素、細胞增殖和細胞凋亡來保護器官和組織。氧化壓力已經被證實和膽結石的形成有很大的關聯，而利用抗氧化劑—褪黑激素可以預防色素膽結石的產生。本篇論文利用部分膽管結紮的動物模式，探討HO-1 在膽結石形成的扮演的角色及是否可以利用血色素氧化酵素的誘導來預防膽結石的形成，再者此保護作用是否和HO-1 抑制細胞凋亡的作用有關。因此我們利用膽管結紮的天竺鼠合併施打HO-1 誘導物—氯化鈷及抗氧化劑-褪黑激素的動物模式，以HO 活性測定及免疫組織染色觀察肝臟HO-1 的表現，肝細胞凋亡狀態則以TUNEL 及Caspase 3 活性測定來評估，並以肝細胞GSSG-GSH 的變化探討氧化壓力的變化。另外，由於HO-1 啟動子微衛星小體之基因多型性對HO-1 基因表現佔重要的影響，因此我們也想探討在臨床檢體HO-1 啟動子微衛星小體基因多型性和膽結石發生率的關係。
　　結果顯示在天竺鼠動物模式進行部分膽管結紮會導致膽結石。在結紮早期肝臟HO-1 活性增加，七天後則回復至與對照組相當。膽管結紮會促成肝臟細胞凋亡的增加。在膽管結紮前24 小時施打單一劑氯化鈷可以誘導HO-1 的產生，提高生存率並預防膽結石形成﹔與每日施打褪黑激素有相同效果。然而我們無法在藥物治療的動物肝臟中看到明顯的細胞凋亡降低，其保護效果可能與抑制細胞凋亡較無關。血清生化肝功能測定及肝臟萃取液氧化壓力評估都顯示天竺鼠長期膽管結紮會有適應性的反應。另外，在人類基因多型性研究中我們未發現HO-1 啟動子微衛星小體基因多型性和膽結石的發生有相關，但因個數太少，無法排除HO-1 基因多型性和膽結石形成的關聯性。總結來說，HO-1 在膽結石致病上扮演一重要角色, 未來應可以作為一個預防膽結石形成的治療策略。

　　Heme oxygenase-1（HO-1）confers cytoprotection against oxidative stress and modulates cellular functions such as cytokine production, cell proliferation, and apoptosis to protect organs and tissues from acute injury. Free radical-mediated oxidative stress has been implicated in the genesis of gallstone and melatonin treatment prevented pigment gallstone formation in guinea pigs. In this study, we aimed to investigate the role of HO-1 in gallstone formation and whether the induction of HO-1 could prevent gallstone formation through antiapoptosis effect in bile duct ligated animal model. The common bile duct ligated guinea pigs were pretreated with CoCl2 as a HO-1 inducer or melatonin. Heme oxygenase activity and HO-1 protein expression in liver were determinated. TUNEL assay and caspase 3 activity assay was performed to investigate the apoptosis in liver. Oxidative stress in liver was detected by oxidized glutathione-reduced glutathione ratio（GSSG/GSH）. In addition, previous studies indicated that HO-1 promoter microsatellite polymorphism could modulate the level of gene transcription. We also studied the correlation of HO-1 promoter microsatellite polymorphism and cholelithiasis in patients with gallstone.
　　We found bile duct ligation led to sludge/stone formation with decreased HOactivity and enhanced apoptosis in liver. Pretreatment with a single dose of CoCl2 24 hours before bile duct ligation or daily injection of melatonin induced HO-1 expression and prevented the stone formation. However, no significant change of apoptosis was detected in pre-treated bile duct ligated groups, indicating that the cytoprotection of HO-1 in this model is not mediated by anti-apoptosis effect. Liver with long-term bile duct ligation displayed increased oxidative stress index and HO-1 induction ameliorated the oxidative stress and as such prevented the gallstone formation. We did not find out the correlation between HO-1 promoter polymorphism and cholethiasis in human so far, but we could not exclude the importance of HO-1 in gallstone formation due to the limited case number. In conclusion, heme oxygenase-1 plays an important role in the pathogenesis of cholelithiasis and may be used as a prophylactic strategy to prevent gallstone formation.

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