探討組蛋白去乙醯酶抑制劑phenylbutyric hydroxamate對免疫細胞的調控與對氣喘小鼠呼吸道發炎現象之影響

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題名:	探討組蛋白去乙醯酶抑制劑phenylbutyric hydroxamate對免疫細胞的調控與對氣喘小鼠呼吸道發炎現象之影響 The modulatory effects of phenylbutyric hydroxamates on the immune cells and airway inflammation in asthmatic mice
作者:	許庭毓 Hsu, Ting-Yu
關鍵詞:	過敏性氣喘 HDAC inhibitor;phenylbutyric hydroxamate
日期:	2015-07-15
上傳時間:	2020-08-28 15:37:11 (UTC+8)
摘要:	過敏性氣喘(allergic asthma)是常見的慢性呼吸道發炎的疾病，常見的症狀為可逆性的呼吸道阻塞以及支氣管痙攣，主要是因為第二型輔助T細胞(type 2 T helper cells, Th2 cells)分泌細胞激素IL-4、IL-5及IL-13造成肺部嗜酸性白血球聚集、支氣管平滑肌收縮以及大量分泌黏液，進而造成患者產生呼吸困難的現象。組蛋白去乙醯化酶(Histone deacetylases，HDACs)是參與表觀遺傳調控的重要酶，可以進而去調控基因的表現。過去研究指出，此類酵素在許多癌症中，都有大量表現的情形；使用組蛋白去乙醯酶抑制劑(histone deacetylase inhibitor, HDACI)可以抑制腫瘤的增生與發炎反應。有研究將HDACI trichostatin A(TsA)應用在小鼠氣喘模式上，發現TsA能減輕氣喘小鼠的呼吸道過度反應(airway hyper-responsiveness, AHR)、黏液的分泌、發炎細胞的浸潤以及Th2型細胞激素的分泌。本研究主旨在於探討hydroxamic acids類的HDACI─PBHA對於參與氣喘疾病生成之免疫細胞(樹突細胞與T細胞)的調控影響，以及PBHA是否能有效減低氣喘發病小鼠的臨床症狀。我們先利用MTT assay檢測不同濃度的PBHA對樹突細胞存活率的影響，選擇對細胞較無毒性的劑量進行後續的實驗；分析PBHA對LPS刺激後的樹突細胞，其細胞激素與細胞表面分子表現的情形，實驗結果發現，樹突細胞之IL-10分泌量有明顯的降低，而前發炎激素TNF-?恁BIL-6則沒有太大的影響，另外對樹突細胞上表面分子MHC class II有抑制其表現的效果。接著我們將PBHA直接作用於經anti-CD3/CD28抗體活化的CD4+ T細胞上，發現PBHA可能具有抑制其增殖的效果。接著我們進一步使用氣喘小鼠動物模式，研究PBHA對於氣喘的治療效果。結果顯示PBHA可以有效減輕小鼠呼吸道阻力的上升與肺部的發炎反應，也可以抑制經過敏原OVA刺激後脾臟細胞的Th2細胞激素IL-4、IL-5及IL-13的分泌；另外也可以降低全身血清中OVA專一性抗體IgE的表現量。 Allergic asthma is a common chronic inflammatory disease of the airways characterized by reversible airflow obstruction and bronchospasm. The inflammatory process in allergic asthma is dominated by type 2 T helper (Th2) cells that produce interlukin-5(IL-5), IL-4 and IL-13, which recruit eosinophils into lung, bronchial smooth muscles constriction and contribute to mucus production. Histone deacetylases are important enzymes of epigenetic regulation that control gene expression. Previous studies have shown that HDACs are found high level in many cancers and the treatment of HDAC inhibitors (HDACIs) can inhibit tumor progression and inflammation. Some studies use trichostatin A(TsA) in asthma animal model found that TsA decrease airway hyper-responsiveness, mucus production, leukocyte infiltration and cytokines production. Another study suggestted that use suberoylanilide hydroxamic acid (SAHA) can induce Foxp3+ Treg cells and decrease transplant rejection in permanent engraftment of cardiac and islet allografts models. In this study we want to investigate the therapeutic effects and immune-modulatory mechanisms of PBHA a kind of HDACI in hydroxamic acids group on asthma. First, we use MTT assay to choose concentration of lower-toxic dose. Then we’ll use LPS and PBHA traet dendritic cells and analysis the cytokine in the supernatant. Next we’ll use fluorescent antibody detect the expression level of surface markers on dendritic cells. We’ll investigate whether dendritic cells treat with PBHA and LPS effect proliferation of CD4+ T. In the future, we will elucidate therapeutic effects and the immune-modulatory role of PBHA in asthma murine model.
描述:	碩士指導教授:李岳倫委員:楊雅倩委員:蕭哲志
資料類型:	thesis
顯示於類別:	[醫學科學研究所] 博碩士論文

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