膽汁淤積指的是膽汁從肝臟排放至十二指腸內受阻的病態情形，發生在許多肝臟疾病中。越來越多的證據指出膽汁淤積引起的肝臟傷害與肝內的氧化壓力提高有關係。最近的研究也指出斥水性的膽酸所引起的肝臟細胞凋亡與內質網壓力的提高有關係。一氧化碳(CO)，是第一型血基質氧化酶 (heme oxygenase-1, HO-1) 分解血基質形成的產物之一。許多研究都指出CO，在抗發炎、抗凋亡的機制中扮演很重要的角色。在體內以及體外的實驗模式中，給予其CO，都具有保護肝臟細胞的作用。因此，本篇研究的目的是利用膽管結紮動動物模式，探討CO 是否提供保護作用；以及其在調控氧化壓力及內質網壓力的關係。利用ICR 小鼠總膽管結紮(BDL)來引發膽汁淤積 Dichloromethane (DCM) 可以被細胞色素CYP2E1 和CYP2B1 代謝，形成CO 與二氧化碳，因此被當作是一種CO 的前趨藥物。小鼠於手術前兩個小時開始，及術後每日口服給予DCM，並分別在第一、四、七天進行犧牲取樣。以血清肝功能指數和組織病理切片來評估DCM 的給予對肝臟的影響。為了進一步探討DCM 作用的機轉，測定血清中的總抗氧化能力和肝臟caspase-3 活性的情形。也利用西方墨點法來偵測肝臟內質網壓力和細胞凋亡的指標性蛋白質的表現。在連續DCM 七天的處理下，膽道結紮小鼠血清之AST 及ALT 活性有顯著的下降 (AST, 463±58 vs. 1270±90 U/L,p<0.05；ALT, 406±25 vs. 961±83 U/L, p<0.05)。在肝臟組織切片的結果也顯示DCM 可以減小凝固性壞死的區域，及減少凋亡細胞的數量。DCM 也使結紮一天小鼠肝臟萃取液的caspase-3 活性下降 (469±21 vs. 1286±93 flu/hr.μg, p<0.05)。而在結紮第七天，DCM 顯著地提高了血清總抗氧化能力 (755±129 vs. 260±19 μmol/L, p<0.05)。肝臟萃取液中，內質網壓力指標性蛋白質 (Grp78 及CHOP) 的表現在結紮七天有明顯上升，而DCM 的給予使之明顯的降低。總結，DCM 的給予可以減少肝臟因膽汁淤積所引起的肝細胞壞死及凋亡，其作用機轉可能是經由降低肝臟的氧化力，內質網壓力，以及減少細胞凋亡路徑的啟動而達成。

Cholestasis is a clinical syndrome resulting from the interruption in the formation and excretion of bile. Growing evidence has suggested that the elevation of intrahepatic oxidative stress plays an important role in cholestasis-induced liver injury. Recent studies indicate that hydrophobic bile acid-induced hepatocytes apoptosis is associated with the elevation of endoplasmic reticulum (ER) stress. Carbon monoxide (CO), one of the products of heme oxygenase-1 (HO-1) mediated heme degradation, has been shown to play a crucial role in anti-inflammatory and anti-apoptotic protection. This study aimed to investigate the hepatoprotective effects of CO and evaluate its role in regulating oxidative and ER stress in cholestatic liver injury. Complete bile duct ligation (BDL) was performed
in male ICR mice to induced cholestasis. Dichloromethane (DCM) was used as a CO pro-drug. Daily oral administration of DCM was performed starting from 2 hours prior to the surgery. Mice were sacrificed at day-1, day-4, and day-7 after the surgery. Serum liver biochemistry tests and liver histology were examined to evaluate the effects of DCM on
liver damage. To further investigate the mechanism of DCM’s effects, serum total antioxidant capacity (TAC) and liver caspase-3 activity were determined. Expressions of
ER stress and apoptosis markers were determined by western blot analysis. Serum levels of AST and ALT were greatly elevated after bile duct ligation, and were significantly reduced by DCM treatment in the ligated mice at day-7 post ligation (AST, 463±58 vs. 1270±90 U/L, p<0.05；ALT, 406±25 vs. 961±83 U/L, p<0.05). Caspase-3 activity in the liver
homogenate were elevated in the BDL mice, and were reduced by DCM treatment at the fist day after ligation (469±21 vs. 1286±93 flu/hr.μg, p<0.05). This reduction of capsase-3
activity was also observed at day-4 and day-7 post ligation. Serum levels of TAC were reduced in the ligated mice, and were marked increased by DCM at day-7 post ligation (755±129 vs. 260±19 μmol/L, p<0.05). BDL induced overexpression of Grp78 and CHOP,whereas DCM treatment down-regulated the expression of these two ER stress markers at day-7 post ligation. DCM treatment also attenuated the coagulation necrosis in the liver of BDL mice, and less number of apoptotic cells were observed. In conclusion, CO administration provided liver protection against cholestasis-induced liver injury through the reduction of oxidative stress, ER stress, and apoptosis.

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