肺上皮細胞重複性受到損傷可能會因為許多肺泡的微環境的改變，促進肺上皮細胞減少以及間質性細胞堆積，導致不正常的細胞修復以及重建，肺間質的組織增厚，造成肺組織喪失氧氣交換的能力，呼吸系統失能，且過多的細胞外基質(Extracellular matrix, ECM)堆積在肺中導致肺纖維化(Pulmonary fibrosis)。促進纖維化因子是影響肺泡微環境之一，其中乙型轉化生長因子(Transforming growth factor-β, TGF-β)與組織發育、致癌以及纖維化有關，也是上皮-間質轉化(Epithelial-mesenchymal transition, EMT)的主要誘導者。EMT是上皮細胞轉變成間質型細胞的過程，在肺損傷後的組織修復與傷疤的形成扮演重要的角色。前胸腺素(Prothymosin α, ProT)是酸性核蛋白，會調節細胞的轉錄、染色質重建以及免疫調節等，在過去實驗室的研究發現在四氯化碳(CCl4)誘導的肝纖維化中，ProT可以調控Smad7 蛋白的表現。因此，我們假設ProT可能通過抑制TGF-β訊息傳遞路徑來抑制肺纖維化，利用博萊黴素(Bleomycin)誘導肺纖維化的動物模式中研究ProT在肺損傷以及纖維化中的致病機轉。我們在細胞實驗上證實在TGF-β誘導後，ProT過量表現的肺上皮細胞中，磷酸化Smad2表現會下降，且被誘導增加的Snail及N-cadherin也因為ProT的過量表現而被抑制了，相反的E-cadherin回升，也發現ProT會抑制細胞爬行的
能力，另外在ProT下降表現的細胞中有一致的證實。在動物實驗方面，首先我們發現在ProT基因轉殖鼠的肺臟中，Smad7的表現量較高。而在小鼠肺纖維化的模式中，發現ProT基因轉殖鼠磷酸化Smad2及纖維母細胞特異性蛋白(Fibroblast specific protein 1, FSP1)的表現量減少，另一方面也發現肺纖維化在一般小鼠較ProT基因轉殖鼠嚴重。綜合以上結果，本篇研究指出ProT藉由增加Smad7的表現來抑制TGF-β誘導的EMT中扮演重要角色，並且可以減少肺纖維化的發生。

Pulmonary fibrosis is the formation or development of excess deposition of extracellular matrix in the lung. Repetitive injury of alveolar epithelium may cause dysregulated repair and aberrant tissue remodeling. Many alterations in the alveolar microenvironment eventually promote loss of alveolar epithelial cells and accumulation of activated fibroblasts and myofibroblasts, leading to progressive fibrosis. Transforming growth factor-β (TGF-β) is one of the profibrogenic cytokines responsible for tissue development, carcinogenesis, and fibrosis. It is also a major inducer of epithelial-mesenchymal transition (EMT). EMT is a process required for epithelial cells undergoing phenotypic changes to mesenchymal counterparts and gives rise to myofibroblasts, which plays an important role in tissue repair and scar formation following epithelial injury. Prothymosin α (ProT) is an acidic nuclear protein and an important regulator of cell proliferation, transcription, chromatin remodeling, and immunomodulation. We have demonstrated previously that ProT can upregulate smad7 protein levels and reduce CCl4-induced liver fibrosis in mice. Therefore, we hypothesized that ProT may play a pivotal role in suppressing pulmonary fibrosis through the inhibition of TGF-β signaling pathway. Here we studied the role of ProT in the pathogenesis of lung injury and fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis. We showed that phosphorylated smad2 levels were reduced in ProT-overexpressing lung epithelial cells after treatment with TGF-β. We also found that TGF-β-induced downregulation of E-cadherin and upregulation of Snail and N-cadherin could be suppressed by ProT overexpression in A549 lung epithelium-like cells. Furthermore, ProT transgenic mice expressed higher levels of smad7 in the lung. Therefore in our animal model, we found that pulmonary fibrosis and fibroblast specific protein 1 (FSP1) were reduced in ProT transgenic mice compared to non-transgenic mice after bleomycin treatments. Taken together, our results suggest an important regulatory role of ProT in the inhibition of TGF-β-induced EMT through the upregulation of smad7.

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