寒熱藥對氣喘鼠模型體質之基因體差異

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Title:	寒熱藥對氣喘鼠模型體質之基因體差異
Other Titles:	Differentail Genomic Expression of Asthma Animal Model in Heat-TCM or Cold-TCM
Authors:	高尚德(Kao,Shung-Te)
Contributors:	中醫學院中醫學系學士班中醫內科學科;中國附醫中醫內科
Keywords:	寒藥;熱藥;體質;小青龍湯;麻杏石甘湯;塵蟎;氣喘;細胞激素;Ma-Xing-Gan-Shi-Tang;Xiao-Qing-Long-Tang;Asthma;Th1/Th2 modulation;Cytokine;Chemokine;Adhesion molecule
Date:	2006-06-30
Issue Date:	2009-09-01 13:36:20 (UTC+8)
Abstract:	氣喘是全球性的重大公共衛生問題，研究指出，引發氣喘最重要的因子乃是過敏反應，其罹患率與致死率在過去二十年中持續增加，由此可見氣喘治療與預防的重要性。氣喘致病機轉中，T-淋巴球對氣喘之形成、調控及氣喘呼吸道慢性發炎反應均扮演重要角色。成熟之輔助性T淋巴球 (T helper lymphocyte)依所分泌的淋巴激素不同可分成Th1及Th2細胞，Th1-參與遲發型過敏反應 (delayed type hypersensitivity)而Th2-參與過敏性發炎反應 (allergic inflammation)。Th2分泌IL-4、IL-13能抑制Th1之活性，相對的，Th1產生的IFN-γ、IL-10對Th2細胞亦具有負迴饋反應。研究顯示氣喘患者呈現Th2細胞增多的趨勢，Th2細胞可經由IL-4、IL-5協助IgE的形成及活化肥大細胞與嗜酸性白血球。因此，在暴露於過敏原後，過敏性氣喘之呼吸道中Th2細胞在調節慢性發炎反應、維持呼吸道過度反應性和控制特異性IgE生成上扮演關鍵角色。最近幾年，影響特異性免疫反應來調控Th1或Th2路徑的因子已廣泛被發現，Th1及Th2細胞是由T輔助性前驅細胞(Th0)於抗原呈現時受其環境與遺傳雙重因素影響下發展而來。研究證據顯示Th1和Th2反應在體內是互相調節的，調節Th1/Th2平衡並使之趨向Th1優勢化，對以因Th2細胞為主的氣喘之治療是合理的策略，亦提供了免疫調節劑發展之方向。目前已知中藥對於免疫系統具調節功效，我們先前的研究也發現中藥方劑可以調節Th1與Th2細胞平衡，熱藥小青龍湯及寒藥麻杏石甘湯是東漢張仲景《傷寒論》治療氣喘的名方，我們發現熱藥小青龍湯能夠降低卵白蛋白誘發氣喘天竺鼠立即性與遲發性氣喘反應，亦能減少塵蟎(Dermatophagoides pteronyssinus, Der p)所誘發之氣喘老鼠肺泡沖洗液的發炎細胞總數及嗜酸性白血球浸潤，調降過敏原誘發肺內淋巴球反應，及降低肺泡沖洗液中CD4+T細胞族群，此免疫調節之功能可能是經由升高CD3+/CD8+與CD4-/CD8-T細胞所致；而寒藥麻杏石甘湯在塵蟎致敏的天竺鼠立即型的氣喘反應中（immediate asthmatic responses，IAR），在第1, 6 及 24 小時有明顯的neutrophil增加，對遲發型呼吸道麼反應，可緩解氣喘天竺鼠立即性反應期之呼吸道阻力，降低呼吸道炎症。對遲發型呼吸道麼反應期的嗜酸性白細胞沒有明顯的抑制作用。在本研究室所建立的動物模式中不僅提供了一個塵蟎過敏老鼠之研究模型，造成Th族群不平衡現象可能是歸因於上述之細胞激素，化學趨化因子(chemokine)及趨合分子(adhesion molecules)之相互調節所造成，也是由寒熱藥在同一種個體產生不同的反應，這樣的差異反應是否決定了對氣喘療效或是不同的體質產生不同的反應。本研究擬延續前項實驗繼續深入探討熱藥小青龍湯或寒藥麻杏甘石對正常老鼠及塵蟎誘發氣喘老鼠肺部之cytokine、cytokineption factor and 鼠之肺部浸潤， chemokine、adhesion molecular、transcription factor、signal transduction associated protein and oncogene廣泛的調節作用，進而影響到免疫組織間的微環境做為比較，基於寒證用熱藥，熱證用寒藥之基本識認，看寒藥及熱藥對氣喘鼠的gene之不同的表現，來探討其寒熱不同的分子層面。 Asthma is a major public health problem worldwide, and asthma morbidity and mortality have increased over the last two decades. Although the reason for this increased incidence is unknown, there is a clear association between atopy and asthma. Antigen-induced IgE production, airway inflammation, and airway hyperresponsiveness have been well documented in patients with allergic asthma and in animal models. Increasing evidence suggests that the Th2-type cytokines IL-4, IL-5, and IL-13, produced by activated CD4+ T cell, play a central role in the pathogenesis of allergic asthma.With the increased understanding of the pathogenesis of asthma, anti-inflammatory therapies have become important therapeutic strategies for asthma treatment. The representative cytokines of Th2 cells are IL-4 and IL-5. IL-4 is the major inducer of class switching to IgE biosynthesis in B lymphocyte; IL-5 is the principal eosinophil-activating factor. IFN-g, which is a representative cytokine of Th1 cells, is known to suppress the development of Th2 cells. Since evidence suggested that the Th1 and Th2 types of reactions are reciprocally regulated in vivo, the modulation of Th1/Th2 balance, namely shifting the balance from Th2 to Th1 dominance, should be a rational strategy for the therapy of allergic asthma. These inbalance maybe decided the response of differental body. There are detailed description of the clinical experiences and prescriptions of asthma in traditional Chinese medicine; (cold drug) Ma-Xing-Gan-Shi-Tang (MXGST), (heat drug) Xiao-Qing-Long-Tang (XQLT) is one of the tradiational Chinese medicines used to treat bronchial asthma and allergic rhinitis for centuries. In our previous research, we found the different response between MXGST and XQLT has bronchodilator and immunomodulatory effects on reducing bronchial inflammation in the allergen-induced murine model. We will evaluate the effects of MXGST and XQLT on gene changes include cytokine and chemokine gene(IL-1？HBIL-6？HBTNF-？H\？HBIFN-？H^？H？HIL-2, IL-4？HBIL-5？HBIL-6？HBIL-9？HBIL-10？HBIL-13), inflammatory signal tranduction gene (NF-？HeB pathway, MAPK pathway), tranciption factor(STAT gene, cMaf gene and GATA gene), cell adhesion molecular (ICAM-1 VACM-1 and E-selectin), and cell cycle-regulatory gene (p21, p53, CD2,？HK..). These data may provide a explain that same body of a disease in the two different property drugs will induce what a different response in the gene level.
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