探討肺上皮之神經生長因子與胸腺基質淋巴生成素於過敏性呼吸道發炎之角色與治療研發

Study on the Role of Epithelial Nerve Growth Factor and Thymic Stromal Lymphopoietin in Allergenic Airway Inflammation and Therapeutic Approaches

10.6342/NTU201602622

陳逸璉

氣喘 ； 呼吸道過度反應 ； 神經生長因子 ； 胸腺基質淋巴生成素 ； 小髮夾型核醣核酸 ； CC趨化因子17 ； 慢載體病毒 ； asthma ； TSLP ； NGF ； shRNA ； CCL17

臺灣大學臨床醫學研究所學位論文

2016年

博士

江伯倫

英文

氣喘為包括環境以及基因特異性等多因子構成的慢性呼吸道疾病，其病理性特徵為呼吸道過度反應(airway hyper-responsiveness; AHR)與呼吸道狹窄。肺上皮細胞為呼吸道第一層防護，其功能為抵禦微生物入侵並引發調節免疫反應，然而，其完整的調控機轉至今仍未清楚解開。 肺上皮細胞經由過敏原或促發炎介質刺激後會釋出神經生長因子(nerve growth factor; NGF)與胸腺基質淋巴生成素（thymic stromal lymphopoietin; TSLP)。研究指出，這兩種細胞激素會高量表現於氣喘患者的肺部沖洗液，並藉由調控免疫反應來參與呼吸道發炎與AHR。然而，此兩種細胞激素之間的關連性至今仍不明瞭。 在本篇論文中，利用慢載體病毒(lentivirus)攜帶可專一抑制特定基因之小髮夾型核醣核酸(short hairpin RNA; shRNA)於卵白蛋白誘發之氣喘小鼠模式來探討此兩種細胞激素在呼吸道發炎與AHR之角色。本篇論文分別探討：（1） TSLP是否參與呼吸道發炎反應以及其可能的機制為何;（2）NGF是否藉由調控神經系統來影響AHR，並利用受器抑制劑作為治療對照組。 第一部份的結果顯示：肺上皮細胞經由TSLP刺激後會增加TSLP受器、CC趨化因子17 （CCL17）與NGF表現量；減弱TSLP在氣喘小鼠之呼吸道的表現量可降低AHR之嚴重程度、藉由降低eotaxin產生量而減少嗜酸性白血球聚集、減少呼吸道樹突狀細胞之活化、減少Th2細胞激素分泌量、降低肺組織中CCL17與NGF分泌量以及substance P表現量。第二部分結果顯示：NGF可透過TrkA受器路徑進而調控AHR以及影響呼吸道之神經纖維分布與活性。受器抑制劑療法可成功降低AHR以及神經纖維分布與活性，但此療法也會造成呼吸道中NGF堆積與增加嗜酸性白血球聚集。 本篇論文證明TSLP在呼吸道發炎的角色以提供TSLP療法應用於過敏性氣喘疾病中之重要性，以及RNAi療法在AHR治療之發展性。

Asthma is a chronic disease, which is contributed by multiple factors including environmental factors and genetic susceptibility, with obvious pathogenic features including airway hyper-responsiveness (AHR) and airway narrow. Airway epithelium defends the invasion from microorganisms and regulates immune responses in allergic asthma but its overall mechanisms are still uncertain. The nerve growth factor (NGF) and thymic stromal lymphopoietin (TSLP) would be produced from airway epithelium after the stimulations of allergens or proinflammatory mediators. They were high expressions in bronchoalveolar lavage (BAL) fluid of asthmatics and have been suggested that these two cytokines mediate in immune responses and probably in AHR. However, the correlation between these two cytokines was still unclear. In this study, we used short hairpin RNA (shRNA), which can particularly silence target gene, in OVA-induced asthma model to reveal the functional roles of the specific cytokine in airway inflammation and AHR. Two parts in this study were whether TSLP mediated in airway inflammation via possible mechanisms and whether NGF mediated in AHR via neural system and the receptor inhibitor as the therapeutic control. In part I, results were found that the expressions of TSLP receptors and CCL17 were regulated by TSLP in airway epithelium in vitro. Attenuated TSLP in asthmatic airways could reduce severity of AHR, diminish eosinophil recruitment by decreasing eotaxin level, down-regulate the activation of airway DCs, decrease secretion of Th2 cytokines, and reduce the expression of epithelial CCL17 in vivo. Furthermore, TSLP induced the production of epithelial NGF in vitro. Attenuated TSLP also reduced NGF level in BAL fluids and expression in airways. In addition, the level of substance P was parallel decreased in the lungs of shTSLP groups. In part II, results were found that NGF could modulate severity of AHR and increase innervations of nerve fibers in airway via NGF- tropomyosin-related kinase receptor A (TrkA receptor) pathway. Although blockage of TrkA receptor could successfully decrease AHR and innervations, this treatment also increase NGF accumulation to augment eosinophil recruitment in airway. This study showed a new function of TSLP in airway inflammation, provided the consequence to TSLP therapy in allergic asthma, and the advantage of RNAi for the potential therapy of AHR.

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