丹皮酚及其衍生物抑制肺纖維母細胞爬行及侵襲之機轉探討

The anti-migratory and invasive effects and molecular mechanism of Paeonol and its derivatives in primary cultured lung fibroblast

徐子雯(Tzu-Wen Hsu)

指導教授 ： 吳俊錡

中山醫學大學/醫學院/醫學研究所/碩士(2017年)

摘要

特發性肺纖維化(idiopathic pulmonary fibrosis)是一種慢性進行性的彌漫性肺間質疾病。廣泛侵犯肺實質、肺泡壁、淋巴、氣管周圍的結締組織而造成纖維化。肺組織受到損傷後影響肺泡微環境的改變，導致不正常的細胞修復，纖維母細胞過度增殖及累積分泌許多的細胞外基質(ECM)，最後出現纖維化。過去研究表示，纖維母細胞增生的程度可以作為預示疾病發展的表現，若能控制肺纖維母細胞增殖、爬行與侵襲能力的藥物，可能有助於控制肺纖維化的病程進展。丹皮酚，是牡丹皮中最重要的活性成分之一。過去研究顯示它具有抗氧化、抗發炎、抗肝纖維化及抗癌的功效。但是並無抗肺纖維化相關之研究。因此，本論文在探討丹皮酚是否有抑制肺纖維母細胞爬行與侵襲的能力。實驗結果顯示，丹皮酚及其衍生物可以抑制肺纖維母細胞的增殖、爬行及侵襲能力，也有抑制間質細胞的標識分子及與遷移有關的金屬基質蛋白酶(MMPs)的能力。綜合上述結果，丹皮酚及其衍生物具有潛力開發為減緩肺纖維化病程進展及疾病惡化之藥物。

關鍵字

特發性肺纖維化 ； 侵襲 ； 金屬基質蛋白酶爬行 ； 丹皮酚

並列摘要

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive diffuse interstitial lung disease. Onset is thought to involve repeated injury to the alveolar epithelial and abnormal tissue repair, resulting in excessive accumulation of fibroblasts, deposition of extracellular matrix components, formation of scar tissue and distortion of lung architecture, eventually leading to respiratory failure. Fibroblast migration into sites of injury plays an important role in the tissue repair process. Moreover, abnormal tissue repair resulting in excessive accumulation of fibroblasts. Therefore, a medicine can inhibit the proliferation, migration and invasion of lung fibroblast, which might to slow the disease progression. Paeonol, a traditional chinese medicine. It's a major phenolic component of Moutan Cortex which anti-inflammatory, anti-tumor, anti-oxidative and anti-liver fibrosis effects. However, the effect of Paeonol on pulmonary fibrosis has never been examined, and the molecular mechanisms of its anti-migration and anti-invasion action remains unknown. In this study, we found that Paeonol and its derivatives inhibited proliferation, migration and invasion in lung fibroblast. Paeonol and its derivatives suppressed the invasion-related matrix metalloproteinases and mesenchymal cell marker, such as N-cadherin, Snail, Slung and Twist. The results indicated that Paeonol and its derivatives might be worthy to be further characterized its therapeutic role in anti-lung fibrosis.

並列關鍵字

Idiopathic pulmonary fibrosis ； Invasion ； Matrix metalloproteinases ； Migration ； Paeonol

參考文獻

46. Lin CC. Recent advances in the diagnosis and treatment of the idiopathic pulmonary fibrosis. J Intern Med Taiwan 2013;24:446-452.

1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788.

2. King Jr TE, Tooze JA, Schwarz MI, et al. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am J Respir Crit Care Med 2001;164: 1171e81. 


3. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 2000; 161:646.

4. Esposito DB, Lanes S, Donneyong M, et al. Idiopathic Pulmonary Fibrosis in United States Automated Claims. Incidence, Prevalence, and Algorithm Validation. Am J Respir Crit Care Med 2015; 192:1200.