臺灣博碩士論文加值系統

中文摘要
過度或者控制不良的發炎反應已經被證實在許多疾病的進程中扮演重要角色，包括像是癌症、心血管疾病、類風濕性關節炎、多發性硬化症、神經性退化疾病等等。樟芝酸（antcin）是種從牛樟芝中分離出來的生物活性物質。在脂多醣（lipopolysaccharide, LPS）誘導的RAW264.7巨噬細胞的體外實驗中發現，antcin B和antcin C並不影響RAW264.7的細胞存活率且會抑制其iNOS和COX-2蛋白質的表現，其中又以antcin C的抑制發炎能力較佳。當我們給予antcin C時，細胞內的TNＦ-α含量會隨著給予量的增加而降低。除此之外，給予antcin C亦能有效降低小鼠肺部發炎模型中肺泡沖洗液（BALF）中的細胞數，降低肺臟組織中的MPO活性，使SOD活性上升，降低BALF中的NO含量且會抑制iNOS和COX-2蛋白質的表現，也抑制BALF中的TNＦ-α、IL-6、IL-1β生成。此外肺部乾濕重比下降，BALF總蛋白質含量下降，與病理切片觀察到發炎細胞減少的結果相符。我們發現antcin C於體內與體外皆是透過抑制NF-κB的表現及關閉有絲分裂蛋白激酶（MAPK）家族ERK1/2和c-JNK、p-38蛋白的表現來抑制發炎反應。有著類似Dexamethasone的作用。因此，antcin C擁有作為未來抗發炎藥物的開發潛能。
關鍵字：牛樟芝，樟芝酸，抗發炎作用，急性肺損傷/急性呼吸窘迫症候群

英文摘要
Antrodia camphorata, a rare and expensive medicinal fungus, has been used as an herbal medicine for drug intoxication for the treatment of inflammation syndromes and liver-related diseases in Taiwan. Antcin B and antcin C are two bioactive compounds from Antrodia camphorata.
In this study, antcin B and antcin C were used on LPS-induced inflammatory response in RAW264.7 macrophage cell line in vitro. The results revealed that antcin B and antcin C can reduce the production of nitric oxide (NO), and inhibit the iNOS and COX-2 protein expression without affecting the cell viability of RAW264.7 cell. Besides, antcin B and antcin C can significantly reduce the intracellular content of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in a dose dependent.
Moreover, this study demonstrates the protective effect of antcin C on LPS-induced acute lung injury (ALI) in mice. Mice were treated with antcin C 1 hour before the intratracheal instillation of LPS challenge model. Lung injury was evaluated 6 hours after LPS induction. Pretreatment with antcin C markedly improved LPS-induced histological alterations and edema in lung tissues. Futhermore, antcin C also inhibited the release of pro-inflammatory mediators such as NO, TNF-α, IL-1β, and IL-6 at 6 hours in the bronchoalveolar lavage fluid (BALF) during LPS-induced lung injury.
Besides, antcin C reduced total cell number and protein concentrations in the BALF. The pulmonary wet/dry weight (W/D) ratio, and myeloperoxidase activity and enhanced superoxide dismutase (SOD) activity in lung tissues. Antcin C also efficiently blocked protein expression of phosphorylation of mitogen-activated protein kinases (MAPKs) and inhibited the degradation of nuclear factor-kappa B (NF-κB) and IκBα.
This is the first investigation in which antcin C inhibited acute lung edema effectively, which may provide a potential target for treating ALI（acute lung injury）、ARDS（acute respiratory distress syndrome）. Antcin C may utilize the NF-κB and MAPKs pathways and the regulation of SOD activity to attenuate LPS-induced nonspecific pulmonary inflammation. Thus, antcin C has capability to develop as an anti-inflammatory newborn drug in the future.

目錄
第一章 緒論 1
第二章 總論 5
第一節、 牛樟芝簡介與文獻回顧 5
第二節、 牛樟芝活性成分簡介 14
第三節、 發炎反應 19
第四節、 RAW 264.7 巨噬細胞 21
第五節、 LPS 22
第六節、 TNF-α 23
第七節、 NF-κB 24
第八節、 iNOS/COX-2 27
第九節、 Mitogen Activated Protein Kinases （MAPK）家族 29
一、 胞外調節激酶 （Extracellular signal-regulated kinase; ERK）…………. 29
二、 C-Jun 胺基端激酶 （C-Jun N-terminal kinase; JNK） 30
三、 p38-再活化激酶 （p38-reactivating kinase; p38） 30
第十節、 HO-1 32
第十一節、 ALI卅ARDS 34
第三章 實驗部分 39
第一節 實驗架構 39
第二節 研究材料 40
一、 藥品與試劑 40
二、 儀器設備與器材 43
第三節 實驗步驟 45
一、 細胞培養 45
二、 藥物配製 48
三、 細胞存活率測試 （MTT assay） 48
四、 一氧化氮 （NO） 生成分析 50
五、 西方墨點法 （Western Blot） 52
六、 小鼠的肺部發炎實驗模式建立 60
七、 統計分析 63
第四章 結果 64
第一節 樟芝酸對於RAW 264.7的細胞毒性及存活率之影響 64
第二節 樟芝酸對 RAW 264.7 細胞產生一氧化氮之影響 65
第三節 樟芝酸在 RAW 264.7 細胞中影響 LPS 所誘發之 iNOS 及 COX-2 蛋白質表現 67
第四節 樟芝酸對 RAW 264.7 細胞之細胞激素影響 70
第五節 樟芝酸對於 LPS 誘導的 NF-κB 路徑影響發炎反應 80
第六節 在RAW 264.7細胞中樟芝酸對LPS誘發的MAPK蛋白質表現量產生的影響 83
第七節 Antcin C在RAW 264.7細胞中促進HO-1的表現 85
第八節 小鼠的肺部發炎模型 88
一、 小鼠病理切片之肺損傷程度變化 88
二、 Antcin C對LPS誘導的急性肺損傷小鼠的肺泡沖洗液細胞計數與MPO活性之變化 91
三、 LPS誘發ALI後小鼠肺部濕乾重比與沖洗液蛋白濃度之變化 96
四、 小鼠肺泡沖洗液發炎相關細胞激素之變化 99
五、 Antcin C在小鼠體內抑制iNOS和COX-2的表現 105
六、 Antcin C在小鼠體內抑制IκBα卅NF-κB的活化 107
七、 Antcin C在小鼠體內抑制MAPK訊息傳遞路徑 109
第五章 討論 111
第六章 結論 116

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