許多因子參與肺部及支氣管發炎反應的過程，例如肺部感染、自體免疫疾病、吸入有害化學氣體或溶劑、放射線治療、及其他不明的原因均與發炎反應相關，甚至引發肺部及支氣管纖維化。其中，氣喘病程中嗜酸性白血球(eosinophil)引發之發炎反應會釋放嗜酸性白血球陽離子蛋白(eosinophil cationic protein; ECP)造成支氣管表皮細胞纖維化。目前已知ECP能與細胞表面醣胺多醣(glycosaminoglycan)，特別是硫酸乙醯肝素蛋白聚醣(heparan sulfate proteoglycans)結合，並透過巨胞飲(macropinocytosis)作用進入人類支氣管上皮細胞。近年研究顯示纖維細胞(fibrocyte)與發炎反應的細胞激素產生吸引作用，導致肺部纖維化。已知急性發炎細胞激素CXCL-12會和纖維細胞之CXCR4受體結合，進而引發纖維細胞的遷移。本研究探討ECP進入細胞後引發的發炎反應，利用即時聚合酶鏈鎖反應(real-time PCR)以及酵素免疫分析法(ELISA)偵測受到ECP刺激的支氣管上皮細胞中細胞激素基因以及蛋白質表現。此外，亦利用細胞穿透試驗(Transwell assay)及微流體晶片(micro-fluidic chip system)實驗測試纖維細胞在發炎環境的趨性，並模擬人類支氣管發炎反應之微環境改變，發現微流體晶片在實驗效率上優於傳統的細胞穿透試驗。本研究顯示在人類支氣管上皮細胞中加入ECP刺激可明顯促進CXCL-12基因及蛋白質表現，更進一步於微流體晶片系統觀察到纖維細胞朝向支氣管上皮細胞遷移的趨性。我們建立一套體外模擬人體血液的循環系統、探討其發炎反應之現象、並發現ECP在支氣管發炎反應中扮演之關鍵角色。

Inflammatory processes related to lung involve multiple factors which may lead to pulmonary fibrosis and lung scarring. Among which asthma causes subepithelial fibrosis in the airway, an eosinophil inflammation process induced by human eosinophil cationic protein (hECP). Our lab has demonstrated that ECP binds cell surface glycosaminoglycan (GAGs), especially heparan sulfate proteoglycans (HSPGs) on bronchial epithelial cells and enters the cells by macropinocytosis. In addition, recent reports indicate that circulating cells (i.e., the fibrocytes) contributing to the evolution of pulmonary fibrosis are induced by increased expression of certain cytokines. For example, an inflammation cytokine CXCL-12, a ligand for CXCR-4, involves in recruitment of fibrocyte to the lung. In this study, the question is what the influence is when ECP enters Beas-2B cells and induces inflammatory response. Here mRNA and protein expression variation of cytokines in Beas-2B cells upon stimulation with ECP was respectively determined by real-time PCR and ELISA. The chemotaxis of fibrocyte under ECP induced lung inflammation was mimicked by transwell and micro-fluidic chip system to monitor microenvironmental changes. Upon treatment with recombinant ECP, both mRNA and protein expression levels of CXCL-12 increased in a dose- and time-dependent manner. Interestingly, fibrocyte were recruited towards Beas-2B cells in both transwell and micro-fluidic lab chip systems, but the latter showed higher efficiency than the former. In summary, we have established a novel in vitro biomimetic microsystem to simulate blood circulation in the body by monitoring microenvironmental changes and mechanisms of inflammatory process. ECP induced CXCL-12 expression plays a critical role in airway inflammation and pulmonary fibrosis.

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