MMP-1,-2,-9 and TIMP-1,-2 在肝臟纖維化及肝硬化的表現 Expression of MMP-1,-2,-9 and TIMP-1,-2 in liver fibrosis and cirrhosis
中文摘要
慢性病毒性肝炎是一個全球性的健康問題，一般並無明顯症狀或只是輕微的症狀 表現，卻可能持續性的使肝臟發炎和發展成肝臟纖維化，約有 20-30% 的慢性肝 病患者會導致肝硬化或肝細胞癌。肝硬化所引起之併發症常是肝病患者之主要死 因，因此，肝硬化的早期診斷是非常重要的。由肝臟星狀細胞所分泌的細胞外間 質在肝臟纖維化的過程中扮演重要的角色，特別是間質金屬性蛋白?（matrix metalloproteinase, MMPs）及金屬性蛋白?之組織抑制因子（tissue inhibitor of metalloproteinase, TIMPs）。我們收集了 30 個因肝細胞癌或轉移性肝癌而做過腫 瘤切除手術之 tumorus and non-tumorus 的肝臟組織。我們將 GAPDH、MMP-1, -2, -9 和 TIMP-1, -2 之 mRNA 以即時聚合?連鎖反應（real-time polymerase chain reaction）分別定量。根據 METAVIR 分類系統將 non-tumorus 之肝臟組織依纖維 化的程度分為 F0-F4，同時偵測肝組織內 hydroxylproline 的分佈，評估 collagen 在 肝組織中的含量。MMP-9 之 mRNA 表現在肝臟纖維化後期（F3 - F4）明顯高於 肝纖維化前期 （F0 - F2）（p < 0.03），然而 MMP-1, -2 和 TIMP-1, -2 之 mRNA 表現在肝臟纖維化的分期中並無差異。肝臟組織中 Hydroxylproline 的分佈，在 肝臟纖維化後期亦明顯高於肝纖維化早期（p < 0.05），並和 TIMP-1（r=0.39, p=0.03），TIMP-2（r=0.39, p=0.03）呈現正相關。我們的實驗結果顯示，MMP-9 mRNA 的表現在早期肝臟纖維化的診斷上扮演著重要的角色。
英文摘要
Chronic viral hepatitis is a global health problem. It is usually clinically silent but may undergo persistent hepatic inflammation and progressive fibrosis, which lead to liver cirrhosis and hepatocellular carcinoma (HCC) in about 20-30 % of patients.
Because patients with advanced cirrhosis carry a grave long-term prognosis, early diagnosis of liver fibrosis and early cirrhosis is of paramount importance. Hepatic extracellular matrix (ECM), which is secreted by hepatic stellate cells (HSC), plays an important role in the hepatic fibrogenesis. We concomitantly collected tumorous and non-tumorous liver tissues from 30 patients who underwent surgical resections for hepatocellular carcinoma or metastatic liver cancers. Real-time polymerase chain reaction (RT-PCR) was performed to detect and quantitatively measure mRNA for GAPDH, MMP-1, -2, -9 and TIMP-1, -2 in these tissue samples. In the non-tumorous liver tissues, hepatic fibrosis was staged by METAVIR system (F0 - F4), and the collagen contents were determined by the hydroxyproline levels. The expression of
MMP-9 mRNA was significantly higher in advanced fibrosis (F3 - F4) than that in early fibrosis or no fibrosis (F0 - F2). (p< 0.03), while the expressions of MMP-1, -2, -3 and TIMP-1, -2 mRNA were not statistically significant. Hydroxyproline levels were also significantly higher in advanced fibrosis than that in early fibrosis (p < 0.05) and positively correlated with TIMP-1 (r=0.39, p=0.03) and TIMP-2 (r=0.39, p=0.03).
Our results showed that the expression of MMP-9 mRNA was valuable in the detection of early hepatic fibrosis.
