肝臟纖維化的病理病變常導致器官功能障礙而致命，臨床上是肝膽腸胃道疾病中被探討的主要課題之一。目前認為肝臟纖維化的過程是組織受到各種不同的慢性刺激所誘發的一種傷口癒合反應。纖維化組織具有過量細胞外基質蛋白的堆積，這些堆積的蛋白常會破壞肝臟的正常結構，最後導致器官病理性破壤。肝癌衍生生長因子(hepatoma-derived growth factor)是一純化自肝癌細胞株培養上清液之生長因子，與陸續發現的另五個相關蛋白組成一組蛋白家族。肝癌衍生生長因子在胚胎發育時期的肝組織中大量表現，被認為在細胞分裂、器官生成、胚胎形成、與腫瘤發生等過程中扮演多功能角色。先前的研究中已證實肝癌衍生生長因子在肝癌組織中有過度表現的現象，其表現程度與肝癌細胞的生長呈正相關，並可作為一良好預後指標性蛋白。由於肝臟纖維化常在肝癌臨床病徵發現之前即已出現，因此本研究主要探討利用膽管結紮手術與注射四氯化碳化學物質所誘發之肝臟纖維化之兩種小鼠動物模式中，肝癌衍生生長因子在肝臟纖維化過程中可能扮演之病理性角色。研究結果發現，肝癌衍生生長因子在這兩種動物模式中的表現量均與纖維化過程呈時間依賴性變化，並且在纖維化肝臟組織主要表現於血管周邊的肝實質細胞中。此外，其表現量亦與肝內乙型轉形生長因子(Transforming growth factor; TGF-β)與第一型前膠原蛋白(pro-collagen type I)的增加呈一致性。在誘發肝臟纖維化前若先行送入攜帶肝癌衍生生長因子基因之腺病毒載體，使其大量表現，則會促使TGF-β表現增加與pro-collagen type I分子過度沉積。在體外作用模式中，發現當肝細胞培養在具有膠原蛋白披覆之培養盤時，可觀察到肝癌衍生生長因子與TGF-β間正向地相互調節彼此之分子表現量。此結果顯示肝癌衍生生長因子與TGF-β間所產生之促纖維化訊息傳遞具膠原蛋白依存性（collagen- dependent）。其很可能在肝臟纖維化初期，即藉由此種惡性循環模式作用而加速肝臟的纖維化病變。再者，以肝癌衍生生長因子重組蛋白作用於培養肝細胞，可顯著地刺激培養肝臟星狀細胞中之BrdU uptake與α-smooth muscle actin、pro-collagen type I分子表現量增加，此意味著肝細胞生成之肝癌衍生生長因子可能藉由paracrine的作用模式，活化肝臟星狀細胞。本研究證實肝癌衍生生長因子在肝臟纖維化過程中扮演著促纖維化的角色，預期在未來利用阻斷肝癌衍生生長因子的作用路徑可發展為預防或治療慢性肝臟疾病之有效策略之一。

Liver fibrosis, a major medical problem with significant morbidity and
mortality, is considered as a wound-healing response to a variety of chronic
stimuli. It is characterized by an excessive deposition of extracellular
matrix (ECM) proteins, which disrupts the normal architecture of liver and
ultimately leads to pathophysiological damage to liver. Hepatoma-derived
growth factor (HDGF), a growth factor originally purified from hepatoma
cells, is highly expressed in fetal hepatocytes and hepatoma. It is known to
play multifunctional roles in mitogenesis, organogenesis, embryogenesis,
and tumorigenesis. Its expression correlates with the proliferating state of
hepatocellular carcinoma (HCC) and serves as a prognostic factor. Since
liver fibrosis frequently occurs prior to HCC development, the specific aim
of this study is to investigate the role of HDGF in the progression of liver
fibrosis by using animal models of mice receiving either bile duct ligation
surgery or carbon tetrachloride administration. Quantitative real-time PCR
and Western blotting analysis showed a significant elevation of HDGF
expression in both models. HDGF levels correlated with progression of
liver fibrosis in a time-dependent manner as well as paralleled with the
expression of other two fibrotic markers, transforming growth factor-b1
(TGF-b1) and pro-collagen type I, in fibrotic livers. Intriguingly, the
over-expressed HDGF protein was localized mainly in perivenous
hepatocytes of fibrotic livers. Besides, adenovirus-mediated HDGF gene
delivery potentiated the production of TGF-b1 and pro-collagen type I,
thereby enhancing the intrahepatic collagen matrix deposits as evidenced
by Sirius red stain and morphometrical analysis. In cultured hepatocytes,
TGF-b1 and HDGF mutually up-regulated their de novo synthesis only
when grown on collagen-coated matrix, strongly suggesting that the
TGF-b1- and/or HDGF-driven pro-fibrogenic signaling is
collagen-dependent and a vicious circle may exist at the initial stage of
hepatic fibrogenesis. Moreover, administration with recombinant HDGF
stimulated BrdU uptake and synthesis of both a-smooth muscle actin and
pro-collagen type I in cultured hepatic stellate cells, implicating that a
mode of paracrinal action lies between these two cell types. In conclusion,
HDGF plays a pro-fibrogenic role during liver fibrosis and blockade of
HDGF pathway may potentially constitute the preventive or therapeutic
strategies for chronic liver diseases.

Abbreviations ……………………… 2
Abstract in Chinese ……………………… 4
Abstract in English ……………………… 6
Introduction …………………………… 8
Materials and Methods ……………………… 25
Results ……………………………… 43
Discussion ………………………… 55
Future Perspective …………………………… 63
References ……………………………… 65
Tables ……………………………… 80
Figures ……………………………… 86
Appendixes (Author's CV and publications) … 117

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