特發性肺纖維化（IPF），是一種慢性、漸進式且往往致命的肺間質纖維化疾病。造成的病因不明，但已知IPF的病理特徵是肺泡上皮細胞受傷之後因大量細胞外基質的堆積而導致肺部結構的破壞，而形成纖維母細胞灶。上皮間質轉換(epithelial-mesenchymal transition, EMT) 是指上皮細胞失去自己的特性，轉換成間質細胞的過程。組成纖維母細胞灶的細胞來源部分認為是肺泡第二型上皮細胞透過上皮間質轉換而來。在上皮間質轉換的過程中，上皮細胞失去自己的特性來獲得間質細胞的行為。一些研究發現，在IPF病人蜂窩肺囊腫上皮下層的區域有大量TGF-β1的表現，能夠促使肺泡第二型上皮細胞進行上皮間質轉換而推進IPF的病程。蜂膠是已經廣泛使用數世紀的傳統醫藥品。先前研究發現蜂膠能在動物模式中減緩心臟肝、腎臟和肺纖維化的情形，但詳細的作用機制尚不清楚。在本篇研究中，我們利用無限增殖的肺泡第二型上皮細胞A549觀察蜂膠在TGF-β1誘發EMT上的影響。我們發現TGF-β1在A549細胞誘發EMT的現象有隨劑量變化的情況，包括改變細胞型態、降低E-cadherin和增加N-cadherin表現、細胞骨架F-actin的重排和增加ROS的產量及細胞移動性。預先給予蜂膠，除了能夠避免TGF-β1在24小時所誘發的EMT，像是維持細胞型態、抑制N-cadherin和ROS的增加、降低F-actin的重排及細胞移動性；蜂膠也抑制TGF-β1活化下游的Smad2及AKT。進一步探討可能的功能性成份，咖啡酸苯乙酯和生松素是蜂膠中的活性物質，分別預給這兩種物質發現無法回復TGF-β1所造成細胞型態的改變。預給咖啡酸苯乙酯的組別發現能抑制TGF-β1所增加的N-cadherin和細胞中F-actin的重排，但卻無法回復TGF-β1所造成細胞型態的改變，說明了或許在蜂膠中尚有其他成分參與在抑制EMT的現象，至於是什麼成分則需要更進一步的分析。總結來說，我們發現蜂膠能夠在A549細胞中抑制TGF-β1誘發的EMT，未來在臨床上可能對特發性肺纖維化的預防或治療有些許幫助。

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal fibrotic lung disease. The etiology is unknown, but the hallmark of IPF is fibroblastic foci, which is formed by alveolar epithelial micro-injuries and followed by deposition of extracellular matrix that results in destruction of the lung architecture. Alveolar epithelial type II cells (type II AECs), which is considered as a sources of myofibroblasts, undergo epithelial-to-mesenchymal transition (EMT) to form fibroblastic foci. During EMT, epithelial cells loss their property to gain the behavior of mesenchymal cells. Evidences show that TGF-β1, which expresses abundant in subepithelial regions of honeycomb cysts of IPF patients, can promote EMT in type II AECs to contribute the progression of IPF. Propolis has been used in folk medicine for centuries. Recent reports show that propolis can prevent fibrosis of heart, liver, kidney and lung in animal model, but the mechanism of propolis in preventing pulmonary fibrosis is still unknown. In this study, we used A549 cells, immortalized type II AECs, to evaluate the effect of propolis on TGF-β1-induced EMT. We found TGF-β1 induced EMT in A549 cells in a dose dependent manner. There were cellular morphological changes, decreased E-cadherin, increased N-cadherin productions, intracellular F-actin rearrangement, increased ROS production, and increased cell motility in TGF-β1-induced EMT in A549 cells. Pretreatment with the natural product of propolis, could maintain the epithelial cells morphology, and reverse the change of N-cadherin, ROS production and decrease cell motility in TGF-β1-treated A549 cells for 24 h. Propolis also prevented TGF-β1-induced Smad2 and Akt activation pathways and Snail expression. Caffeic acid phenethyl ester (CAPE) and pinocembrin are the active components of propolis. Respective pretreatment with these two components of propolis had no inhibitory effect on TGF-β1-induced cellular morphological change in A549 cells. CAPE inhibited the changes of N-cadherin expression and reduced the formation of F-actin, still it could not reverse TGF-β1-induced fibroblast-like morphology. These results suggest that there may have other components in propolis involved in the inhibitory phenomenon of TGF-β1-induced EMT in A549 cells. In summary, our results showed propolis prevented TGF-β1-induced EMT in immotalized type II AECs, which may have the clinical application in the prevention and/or treatment of idiopathic pulmonary fibrosis (IPF).

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