2014-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647362摘要：我們先前的研究成果顯示，慢性阻塞性肺病（COPD）病人體中會有胎盤生長因子（PlGF）上升的現象。而利用PlGF 過度表現與PlGF 剔除的基因轉殖鼠，我們證明PlGF 在鼠的彈性纖維蛋白酶肺氣腫模式扮演重要角色。本計畫的中心假說為： 呼吸道上皮細胞為彈性纖維蛋白酶或是香菸暴露後產生PlGF 的主要細胞來源，而PlGF 的增加為發生肺氣腫以及COPD 的根本機轉。為證明此一假說，本計畫有四個重要的研究目的。第一：探討在接觸彈性纖維蛋白酶後，鼠的呼吸道上皮細胞是否為PlGF 的主要來源細胞。第二：以野生型及PlGF 剔除鼠，探討彈性纖維蛋白酶誘發之PlGF 是否涉及鼠的肺氣腫發生過程。第三：探討人的呼吸道上皮細胞是否為COPD 病人體中PlGF 上升的主要細胞來源，而此一PlGF 上升之表現是否與COPD 病人肺內細胞凋亡程度有關。第四：探討當人的呼吸道上皮細胞暴露於香菸或是彈性纖維蛋白酶後，是否會表現出PlGF。本研究包含人類與鼠的活體內(in vivo)與活體外(in vitro)模式，能明確的探討PlGF 參與肺氣腫病因學的機制。藉由集中探討PlGF 及其下游訊息傳遞，本研究的成果將可作為未來新的COPD 治療基石。<br> Abstract: Our preliminary data have demonstrated the elevation of placental growth factor (PlGF) in patients with chronic obstructive pulmonary disease (COPD). In addition, animal models with PlGF overexpression and PlGF knockout mice have demonstrated the participation of PlGF in elastaseinduced emphysema mouse model. The central hypothesis of this application is that respiratory tract epithelium is responsible for PlGF production in response to elastase and/or smoke exposure, and this induction is essential for the pathogenesis of emphysema/COPD development. To elucidate the hypothesis, four Specific Aims are proposed. Specific aim 1 is to test whether or not mouserespiratory epithelial cells are responsible for PlGF production in response to elastase treatment. Specific aim 2 is to test whether or not if elastase-induced PlGF is involved in the pathogenesis of mouse emphysema, using both wild-type and PlGF KO mice for the study. Specific Aim 3 is to test whether or not human respiratory epithelial cells are responsible for the elevated PlGF production in patients of COPD and this elevation is correlated with the presence of apoptotic cells in these human lungs. Specific Aim 4 is to test in vitro if PlGF is induced in human respiratory epithelial cells in response to smoke and/or elastase treatment. These studies with a combination of human and mouse in vivo and in vitro models will provide the mechanistic basis on how PlGF is induced and participated in emphysema. The outcome of such a study can also serve as the therapeutic basis for the treatment of COPD patients on targeting PlGF reduction and its mediated signaling.慢性阻塞性肺病胎盤生長因子彈性纖維蛋白細胞凋亡細胞自噬chronic obstructive pulmonary diseaseplacental growth factorelastaseapoptosisautophagy