在臺灣地區膽汁淤積肝疾病尤其是肝內膽管結石/膽管炎較為常見，其特性為肝膽道阻塞以及漸進式的造成肝纖維化。然而，目前造成膽管炎致肝損傷的真正機制仍然不明。在嚴重膽汁淤積病人中，因膽汁流速的降低因而感染性併發症經常發生，因此革蘭式陰性桿菌外膜的成份脂多糖 (LPS)，可能流入週邊循環而造成破壞性的內毒素血症。因為CD14存在細胞表面之醣磷脂醯肌醇錨定蛋白質，可作為LPS受體，會與內毒素結合並啟動活化細胞並釋放發炎性細胞素。然而在膽汁鬱滯疾病中，CD14基因表現在肝臟中的調控機轉及引發肝臟損害的機制，目前還尚未被闡明。
膽道閉鎖為肝內外膽管完全阻塞閉鎖，是典型新生兒膽汁淤積的疾病；因為膽汁流速下降，膽道閉鎖病患經常也會併發感染和內毒素血症。因此本研究的第一個目標：探討膽道閉鎖的病患中，內毒素的含量及其CD14的表現。我們收集膽道閉鎖的早期接受葛西氏手術 (KP)後接受門診追蹤，膽道閉鎖晚期接受肝移植和先天性膽總管囊腫患者的血漿，測定血漿的內毒素與及可溶性CD14之含量，並利用免疫組織化學染色和原位雜交分析肝組織中的 CD14 基因與蛋白質的表現和內毒素含量。結果發現：早期膽道閉鎖病患肝臟中CD14 mRNA和血漿中CD14蛋白質表現比膽道閉鎖晚期者高；但血漿中內毒素濃度，不管是膽道閉鎖早期或晚期，他們都明顯比一般人高出許多。此外，我們以結紮膽管大白鼠做為阻塞性黃疸實驗模式，證實鬱滯性肝損傷CD14及內毒素的相互關係，結果也顯示膽管結紮的大鼠肝組織中內毒素與CD14也都明顯上升。雖然CD14是人類肝臟細胞產生的急性期蛋白質，但CD14基因表現在肝臟中的調控機轉，鮮少為人知。
然而CD14可調控發炎機制以對抗革蘭氏陰性細菌，已經被證實與膽道閉鎖的發生及病程有關。所以，我們推測LPS可能刺激肝細胞表現CD14，藉以移除內毒素和增加發炎性反應，因此這項研究的第二個目的：希望探討內毒素對CD14基因的調控，以釐清膽汁鬱滯產生CD14之病理機轉。在體外以西方轉漬，即時定量聚合酶鏈反應和啟動子活性測定，探討C9 大鼠肝上皮細胞和HSC T6 肝星狀細胞，在LPS誘導下 CD14表現的變化；而體內研究在膽管結紮兩週的大鼠膽管注射LPS，比較CD14 表現和內毒素敏感性。結果顯示：C9 大鼠肝細胞中，LPS 大幅增加 CD14 蛋白質/mRNA 表現和啟動子活性，但在HSC T6 肝星狀細胞則不受影響。在膽管結紮的大鼠會引起血漿中AST、 ALT和 膽紅素增高，注射內毒素經3 h後，血漿中除了AST、 ALT 、 膽紅素外，發炎因子TNFα 、MCP-1也會大幅增加；同時膽管結紮的大鼠注射內毒素， 24 小時內的死亡率明顯高於對照組。在膽管結紮的大鼠注射內毒素經3 h後，CD14 表現和內毒素都明顯增加；然而在對照組大鼠經注射內毒素後雖然內毒素增加，但CD14的表現卻沒有增加。因此我們認為內毒素可以刺激肝臟CD14 表現，輔助內毒素之清除，但在膽汁鬱滯CD14的大量表現會增加肝細胞對內毒素敏感性和發炎性反應。
總而言之，膽道閉鎖血漿內毒素和可溶性 CD14 表現大幅增加，意味著在膽道閉鎖早期內毒素參與刺激肝細胞CD14產生為了去除內毒素；然而膽道閉鎖晚期內毒素聚積可能導致肝損傷和減少可溶性 CD14 的合成。我們同時證實膽汁淤積和LPS可刺激肝臟中 CD14 表現，會增加結紮大鼠的內毒素敏感性，引發發炎反應進而導致器官衰竭和致死反應。

Cholestatic liver disease, particularly hepatolithiasis/cholangitis, characterized by obliteration of hepatic bile ducts and progressive liver fibrosis is highly prevalent in Taiwan. However, the underlying mechanism of cholangitis-induced liver injury remain uncertain. Because of decreased bile flow, infectious complications occur frequently in severe cholestatic patients. Therefore, lipopolysaccharide (LPS), the product of gram-negative bacilli, may flow into the peripheral circulation and cause damaging endotoxemia in cholestasis. CD14, a glycosylphosphatidylinostol- anchored LPS receptor binds endotoxin to initiate cell activation and release of inflammation cytokines. However, little literature documents the proportional change of CD14 in the liver and the consequent pathogenetic effects on cholestatic and LPS-induced liver injury.
Biliary atresia (BA) is a typical neonatal cholestatic disease, characterized by obliteration of intra- and/or extra-hepatic bile ducts. Because of decreased bile flow, infectious complications and damaging endotoxemia occur frequently in patients with BA. The first aim of this study was to investigate endotoxin levels in patients with BA and the correlation between endotoxin levels and CD14 expression. The plasma levels of endotoxin and soluble CD14 were measured with a pyrochrome Limulus amebocyte lysate assay and enzyme-linked immunosorbent assay in patients with early-stage BA underwent Kasai procedure (KP), in patients who were jaundice-free post-KP and followed-up at the outpatient department, in patients with late-stage BA when they received liver transplantation, and in patients with choledochal cysts. The expression of CD14 mRNA, protein and endotoxin in liver tissues were analysis by immunohistochemical stain and in situ hybridization. The results demonstrated a significantly higher hepatic CD14 mRNA and soluble CD14 plasma levels in patients with early-stage BA than those with late-stage BA. However, plasma endotoxin levels were significantly higher in both the early and late stages of BA relative to controls. Furthermore, correlation between CD14 expression and endotoxin levels in rats following common bile duct ligation was also investigated. In rat model, both endotoxin and CD14 levels were significantly increased in liver tissues following bile duct ligation. Human hepatocytes have been demonstrated to produce CD14 which acts as an acute phase protein, whereas little literature documented the regulation mechanisms of CD14 gene expression in liver.
CD14 mediates host immune reactions in response to gram-negative bacteria and has been linked to the development and disease progression in BA. Therefore, we propose that LPS may stimulate hepatocytes to express CD14 for removal of endotoxin and facilitate liver inflammation. The second aim of this study was to investigate the mechanism underlying LPS-induced upregulation of CD14 and the pathophysiological role of CD14 production during cholestasis. In vitro studies of LPS induced CD14 expression in C9 rat liver epithelial cells and HSC-T6 hepatic stellate cell line was quantified by Western blotting, qRT-PCR and promoter activity assay. To verify whether CD14 expression was linked to endotoxin sensitivity, biliary LPS administration was performed on rats two weeks after undergoing bile duct ligation or a sham operation. LPS significantly increased CD14 protein and mRNA expressions and promoter activity in C9 rat hepatocytes, but not in HSC-T6 hepatic stellate cell line. Experimental cholestasis induced by BDL significantly raised baseline levels of AST, ALT, and T-Bil. After 0.5 mg/kg LPS administration for 3 h, the levels of AST, ALT and T-Bil were all significantly elevated. LPS administration increased of TNFα and MCP-1 levels at 3 h in both sham-operated and BDL-challenged rats. The levels of TNFα and MCP-1 in BDL group were significantly higher than in sham-operated group. The mortality within 24 h in the BDL animals was higher compared to the sham-operated group. CD14 expression and endotoxin levels were significantly increased after LPS administration in BDL rats. In contrast, although endotoxin levels were increased in sham-operated rats with LPS administration, no increase in CD14 expression was found. We found LPS stimulation upregulated hepatic CD14 expression during cholestasis to increaseendotoxin sensitivity and host proinflammatory reactions.
In conclusions, the significant increase in plasma endotoxin and soluble CD14 levels during BA implies a possible involvement of endotoxin stimulated CD14 production by hepatocytes in the early stage of BA for removal of endotoxin; whereas, endotoxin accumulation likely induced liver injury and impaired soluble CD14 synthesis in the late stages of BA. Cholestasis and LPS stimulation upregulated hepatic CD14 expression may lead to increased endotoxin sensitivity and in addition to promote inflammatory reactions to cause organ failure and lethality. Imbalance of endotoxin accumulation or clearance and sCD14 production in liver parenchymal cells is implicated in human and animal models of cholestatic liver injury.

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