- 學位論文
阿魏酸對於呼吸道發炎氣喘動物模式調控機制之探討
Study on the mechanisms of modulatory effects of ferulic acid on airway inflammation in murine model of asthma
摘要
Ferulic acid (FA, 阿魏酸)為多酚類物質，不僅存於穀類與蔬果當中，亦是中草藥當歸與川芎的有效成分之一。研究指出，因FA具有優越的抗氧化和抗發炎的能力，因而有利於預防癌症、降血脂、調節血糖及延緩腦神經退化疾病等作用。然而FA的活性成分是否可以用來改善過敏疾病的可行性並不清楚，因而其調控免疫系統反應的機制是很值得探討與研究的。本研究利用體外培養的小鼠骨髓衍生性樹突細胞，在LPS刺激下與不同濃度FA共同培養，實驗結果發現隨著給予FA的濃度增加，樹突細胞之IL-12分泌量也隨之提升，且在高劑量FA濃度下，亦可明顯提升IL-23分泌但會抑制 IL-10的製造；此外前發炎激素TNF-α、IL-1β與IL-6則是分泌量下降。FA亦可有效提升樹突細胞上表面分子MHC classⅡ、CD40、CD80和CD86的表現，並且降低樹突細胞吞噬抗原的能力，顯示FA可促進樹突細胞之活化與成熟。此外，FA可刺激樹突細胞表現較高量的Notch ligands：Delta1和Delta4，而Jagged1基因表現則是受到抑制的情形。而受FA刺激後的樹突細胞可促進Th1細胞的分化與生成，並使其大量分泌IFN-γ。另將FA應用於預防和治療氣喘小鼠動物模式上，綜合實驗結果顯示，FA可有效降低血清中OVA專一性抗體IgG1與IgE的表現量、提升IgG2a表現量，且能明顯減輕氣喘動物的呼吸道阻力，降低嗜酸性白血球在肺部的聚集，促進IFN-γ的生成以及減少Th2細胞激素IL-4、IL-5、IL-13和前發炎細胞激素TNF-α、IL-1β、IL-6的分泌量。由此我們推測：FA主要可活化樹突細胞來調控小鼠體內T細胞分化成Th1細胞，以藉由多量的IFN-γ分泌來抑制Th2細胞反應，並在配合抑制發炎激素的作用下，共同達到減輕氣喘症狀的效果。FA對於氣喘症狀同時具有預防與治療之功效，將有利於發展成為改善過敏體質之保健食品及藥物。
並列摘要
Ferulic acid (FA) is a phenolic compound abundant in various vegetables and fruits. Moreover, FA is an effective component of Chinese medical herbs such as Angelica sinensis and Ligusticum chuanxiong. It has been reported that FA has antioxidant activity and anti-inflammatory effect which may offer beneficial effects against free radical-related diseases such as cancer, cardiovascular disease, diabetes and neurodegenerative disorders. However, the immune-modulatory effects of FA on immune cells are not well studied. In this study, we first examined the effects of FA on dendritic cells (DCs). Our data showed that FA enhanced the production of IL-12 and IL-23 when DCs were stimulated with LPS. FA also increased the expressions of MHC classⅡ, CD40, CD80 and CD86 on DCs. On the other hand, Delta1 and Delta4 mRNA expressions were increased but Jagged1 expressions were decreased in FA-treated DCs. In addition, FA-treated DCs markedly enabled T cells to develop into IFN-γ-secreting Th1 cells. These results indicated that FA may modulate the function of DCs and promote the differentiation of Th1 cells in vitro. Furthermore, we use OVA-induced asthmatic animal model to investigate the preventive and therapeutic effects of FA in allergic disease. We observed that FA efficiently enhanced the production of OVA-specific IgG2a, and reduced the expression levels of OVA-specific IgE and IgG1.The administration of FA inhibited the development of airway hyper-responsiveness (AHR), airway eosinophilia and Th2 responses. We also found that FA enhanced IFN-γ production and suppressed the secretion of pro-inflammatory cytokines. Taken together, we suggested that FA-treated DCs could inhibit Th2-induced asthma by enhancing the generation of Th1 cells in vivo. Therefore FA might be used as a novel agent to treat allergic diseases in the future for asthma.