瀰漫性肺間質性肺疾病 (Interstitial Lung Disease) 是一種由多種病因所引起的肺破壞性疾病，是以肺泡炎、間質性肺炎、肺泡上皮受損及膠原異常聚集亦即肺纖維化為特徵的慢性疾病，主要症狀為呼吸困難，最終導致呼吸衰竭而死。目前肺纖維化的治療藥物為類固醇，免疫抑制劑和抗纖維化藥物（秋水仙鹼），但這些藥物治療效果不彰且常伴隨著嚴重的副作用。所以，尋求有效以及低副作用的新藥是刻不容緩的議題。本研究在探討中草藥萃取物抗肺纖維化之功效，我們建立了以 bleomycin 誘發之 C57BL/6 小鼠肺纖維化之疾病模式，再以中草藥萃取物包括真菌類萃取物 (HD1-EH2、HD1-OH 與 HH-1) 餵食特定時間後，進行肺功能評估、前肢握力測試、肺部病理組織切片來探討測試藥物對 bleomycin 誘發肺纖維化之抑制功效。數據顯示處理 bleomycin 之小鼠其肺功能顯著較差，前肢握力亦較弱，肺部病理組織結果顯示，肺泡結構受到破壞，並且有大量的 collagen 沉積，顯示確實有纖維化的趨勢。而在評估藥物對 ILD 小鼠之作用效果則分成二部份: (一) 在抗纖維化之效果方面，HD1-EH2、HD1-OH 與 HH-1 處理組皆可以有效減緩 bleomycin 所誘發之肺間質 collagen 和 extracellular matrix (ECM) 的堆疊並減少其肺泡間質增厚之情形，而在這些餵食組中，Prednisolone (早期臨床用藥) 之效果較不顯著。 (二) 在肺功能以及前肢握力分析方面，HD1-OH 組並不能緩解 bleomycin 所造成的肺部通氣障礙，但卻能增強 bleomycin 小鼠的肌握力，而其餘測試藥物皆可有效降低 bleomycin 所造成的肺部阻力，並能舒緩肺部通氣障礙和增強原先被 bleomycin 所破壞之肌握力。總體結果來說，prednisolone 不會增強小鼠肌力，但可顯著抑制 bleomycin 所誘發的發炎反應以及緩解肺功能障礙，但對於後期的纖維化進展並無明顯幫助 ; HD1-OH 組雖然沒有抑制發炎之功效，卻能提升疾病小鼠之肌力，趨緩疾病小鼠發肺泡間質增厚之情況。真菌萃取物 (HD1-EH2、HD1-OH 與 HH-1) 皆可有效改善疾病鼠之肺功能障礙與前肢握力低落。這些標的中草藥或許可在未來保健食品的研發上進行更深入的研發。

Idiopathic pulmonary fibrosis (IPF), a lung destructive disease majorly caused by chronic inflammation, can lead to dyspnea, collagen deposited, lung fibrosis, respiratory failure and eventually death. The current medications for pulmonary fibrosis including steroids, immunosuppressor and anti-fibrotic drugs usually, have severe adverse effects. The searching for new compounds with higher therapeutic effect and lower adverse effects is urgently required. In this study, we examined the potential therapeutic effects of fungal extracts including HD1-EH2, HD1-OH and HH-1 in a C57BL/6 mice IPF model induced by bleomycin. Our results showed that these fungal extracts exhibited distinguished therapeutic effects in bleomycin-induced mouse IPF model. The administration of HD1-EH2, but not HD1-OH, drastically reduced the levels of cytokines such as TNF-α, IL-6 and neutrophil induced by bleomycin, resembled the effects of prednisolone, indicating an anti-inflammatory effect of fungal in a mice IPF model. On the contrary, all three fungal extracts HD1-EH2, HD1-OH and HH-1 significantly alleviated bleomycin-induced lung fibrosis such as collagen deposition and rescued lung functionality via reducing airway resistance primed by bleomycin in comparison with prednisolone in the IPF model. Furthermore, orally feeding of either HD1-EH2, HD1-OH or HH-1 extract of fungal effectively recovered the weight-loss and grip-ablation induced by bleomycin. Conclusively, our results clearly indicate that the extracts of fungal effectively ameliorate both inflammation and fibrosis induced by bleomycin in a mice IPF model. It might be worthwhile to further identify the active ingredients and elucidation of underlying mechanisms of fungal in bleomycin-induced IPF model.

目錄.....................................Ⅰ
表目錄..................................Ⅲ
圖目錄..................................Ⅳ
中文摘要.................................1
英文摘要.................................3
第一章 前言............................4
第一節 何謂肺纖維化 (lung Fibrosis) ........................................4
(一) 病徵............................5
(二) 危險因子........................6
(三) 免疫系統與纖維化.................9
第二節 特發性肺纖維化之流行病學調查......................................14
第三節 肺纖維化之臨床分類..............16
第四節 治療方法.......................17
(一) 西藥治療肺纖維化之研究...........17
(二) 中醫對肺纖維化之研究.............25
第五節 肺纖維化疾病模式之建立...........27
第二章 研究動機與假說...................34
第三章 材料與方法................................................................................36
第一節 實驗材料..............................................................................36
(一) 待測藥物與中草藥萃取物................................................36
(二) 實驗試劑與耗材................................................................36
第二節 實驗方法與步驟..................................................................38
(一) 實驗動物與飼養環境........................................................38
(二) 實驗設計............................................................................38
(三) 實驗架構............................................................................40
(四) 實驗評估項目....................................................................40
(五) 動物試驗分組設計............................................................41
(六) 實驗步驟............................................................................43
第三節 統計分析..............................................................................47
第四章 實驗結果....................................................................................48
Part Ι : HD1-EH2 及 HD1-OH 對 bleomycin 所誘發發炎之影
響..............................................................................................48
Part Ⅱ : HD1-EH2 及 HD1-OH 對 bleomycin 所誘發之肺纖維化
之影響....................................................................................52
Part Ⅲ : HH-1 對 bleomycin 所誘發之肺纖維化之影響................60
第五章 討論............................................................................................67
第六章 結論............................................................................................74
圖表..........................................................................................................75
第七章 參考文獻..................................................................................110

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