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  • 學位論文

在潰瘍性結腸炎小鼠模型中探討白頭翁湯的分子機制

Investigation of the molecular mechanism underlying the Pulsatilla decoction in dextran sulfate sodium-induced colitis mouse model

指導教授 : 游偉絢
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摘要


腸道發炎是潰瘍性結腸炎 (ulcerative colitis) 一個典型的病徵,臨床上潰瘍性結腸 炎的治療常以抑制腸道內異常發炎反應作為治療方針。白頭翁湯 (Pulsatilla decoction) 為一傳統中藥,也是亞洲國家中醫師用以治療潰瘍性結腸炎的處方之一, 然而目前尚不清楚白頭翁湯是透過何種機制抑制腸道發炎。因此,本篇論文中, 我們將葡萄糖硫酸鈉 (dextran sulfate sodium) 添加至小鼠的飲用水誘發潰瘍性結腸 炎,並且餵予小鼠白頭翁湯,探討其在潰瘍性結腸炎小鼠模型中的分子機制。我 們發現在餵予小鼠白頭翁湯後,會有較少的先天免疫細胞浸潤到大腸,使得腸道 發炎的現象較為趨緩。並且,在潰瘍性結腸炎小鼠模型中,嗜中性白血球與巨噬 細胞浸潤的程度與促發炎細胞激素介白素-1β 與腫瘤壞死因子-α 的量呈現正相關。 在免疫螢光染色實驗中,我們進一步觀察到腸道中浸潤的白血球與巨噬細胞會表 現基質金屬蛋白酶-7 (matrix metalloproteinase-7, MMP-7) 。有趣的是,當白頭翁湯 減少腸道中嗜中性白血球與巨噬細胞的浸潤時,活化型 MMP-7 的蛋白表現量也會 隨之下降,顯示在潰瘍性結腸炎小鼠模型中,白頭翁湯由 MMP-7 調控免疫細胞聚 集的重要性。整體來說,我們的研究提供白頭翁湯在抑制人類潰瘍性結腸炎中可 能參與的一種分子機制,並且指出抑制 MMP-7 可能可以作為潰瘍性結腸炎一有效 的治療方針。

並列摘要


Intestinal inflammation is considered to be an important characteristic of ulcerative colitis (UC) and the current medical treatments of UC are usually proposed to suppress abnormal intestinal immune responses. Pulsatilla decoction (PD), a traditional Chinese medicine, is frequently used in UC treatments in Asian countries; however, the mechanism of the action of PD remains unclear. In the present study, the mechanism of the action of PD is elucidated in dextran sulfate sodium (DSS)-induced colitis mouse model. In DSS-induced colitis mouse model, the administration of PD attenuates the intestinal inflammation through suppression of colonic infiltration of innate immune cells. In addition, the level of neutrophil and macrophage infiltration is consistent with the level of pro-inflammatory cytokines, interleukin-1β and tumor necrosis factor-α, in colonic tissues in DSS-induced colitis mouse model. The immunofluorescence double staining further reveals that matrix metalloproteinase-7 (MMP-7) is expressed by the infiltrating leukocytes, including macrophages. Noticeably, the reduced neutrophil and macrophage infiltration is accompanied by a downregulation of the protein level of active MMP-7 in PD treatments, which identifies MMP-7 as an important regulator of leukocyte recruitment in intestinal inflammation underlying PD in DSS-induced colitis mouse model. In conclusion, these findings provide a potential molecular mechanism underlying PD in UC and indicate MMP-7 inhibition as a promising therapeutic approach in UC therapy.

參考文獻


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