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

陳逸璉

doi:10.6342/NTU201602622

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探讨肺上皮之神经生长因子与胸腺基质淋巴生成素於过敏性呼吸道发炎之角色与治疗研发

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

陈逸琏 , 博士　　导师：江伯伦　　

英文 DOI： 10.6342/NTU201602622

气喘；呼吸道过度反应；神经生长因子；胸腺基质淋巴生成素；小发夹型核醣核酸； CC趋化因子17 ；慢载体病毒； asthma ； TSLP ； NGF ； shRNA ； CCL17

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摘要 │ 参考文献 (238) │ 国际计量

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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.

参考文献 ( 238 ) 〈TOP〉

"Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007." J Allergy Clin Immunol 120(5 Suppl): S94-138.
连结：
Abram, M., M. Wegmann, V. Fokuhl, S. Sonar, E. O. Luger, S. Kerzel, A. Radbruch, H. Renz and M. Zemlin (2009). "Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation." J Immunol 182(8): 4705-4712.
连结：
Al-Shami, A., R. Spolski, J. Kelly, A. Keane-Myers and W. J. Leonard (2005). "A role for TSLP in the development of inflammation in an asthma model." J Exp Med 202(6): 829-839.
连结：
Ansel, K. M., D. U. Lee and A. Rao (2003). "An epigenetic view of helper T cell differentiation." Nat Immunol 4(7): 616-623.
连结：
Banchereau, J. and R. M. Steinman (1998). "Dendritic cells and the control of immunity." Nature 392(6673): 245-252.
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引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。