臺灣博碩士論文加值系統

急性肺損傷(Acute lung injury; ALI)是造成患者死亡一個重要的成因。如何抗發炎的治療或是改善ALI患者的預後是重要的課題，己有許多文獻指出中醫藥在對抗肺部急性發炎有其成效，而銀翹散便是其中對抗肺部急性發炎重要的方劑，但其抗發炎的機制仍然不清楚。
為了研究銀翹散對抗肺部急性發炎的機制，我們以氣管投與LPS誘發老鼠肺部急性發炎，同時餵食銀翹散，結果發表不論在肺部發炎的病理組織上、中性白血球的浸潤數量、肺部水腫指標及一氧化氮分泌的量上，皆可見到銀翹散有減緩肺部發炎的成效。我們以ELISA 及 RT-PCR 來偵測各種發炎相關的細胞激素及趨化因子，如TNFα、IL-1β、 IL-6、KC、MCP-1及MIP-2，銀翹散皆有壓制的作用，同時我們也發現銀翹散可誘發大量的抗發炎細胞激素IL-10的分泌。我們利用鼠巨噬細胞RAW 264.7針對TNFα及IL-10 進行體外研究。銀翹散、銀花、連翹及牛蒡對LPS誘發產生TNF-α有明顯壓抑作用，荊芥、薄荷及淡竹葉少許壓制作用。而銀翹散及金銀花可以增加LPS誘發分泌IL-10。
由銀翹散的HPLC成份分析中，找到銀翹散指標成分綠原酸、木犀草素、牛蒡素及橙皮素，其中最大量的成份為綠原酸，我們也證實綠原酸會增加LPS誘發RAW 264.7分泌IL-10；另外我們也發現橙皮素可抑制A549及THP-1的TNFα、IL-1β、IL-6、IL-8的分泌，同時結果也顯示橙皮素可抑制發炎細胞的附著作用及ICAM-1與VCAM-1的表現。我們進一步發現銀翹散橙皮素可減少NF-κB與AP-1對其控制序列結合作用，並且橙皮素可阻斷IκB 及MAPK 路徑。因此，銀翹散有抑制LPS造成的肺部發炎作用及免疫調節作用，有助於急性肺部發炎的治療。

To investigate the effects of Gingyo-san (GGS), traditional Chinese medicinal formula, on the acute lung inflammation induced by LPS in vivo. Mice were challenged with intratracheal LPS before with treatment GGS or vehicle. In Lung morphology, GGS is better than Xia-Bai-San (XBS) and Hesperidin that reducing the infiltration of activated polymorphonuclear neutrophils in the airways, decreasing pulmonary edema, reduced nitrosative stress, and improved lung morphology. ELISA or RT-PCR detected the expression of cytokines in BALF and lung tissue. The mechanism of these benefits by treatment GGS including attenuating expression TNFα, IL-1β, IL-6, KC, MCP-1, MIP-2, iNOS, and activation of nuclear factor (NF-κB and AP-1) in BALF and lung tissue. Particularly, GGS also enhanced the anti-inflammatory cytokine (IL-10) and limited the acute lung inflammation. In vitro, HES suppressed the expression of IL-8 on A549 cells and THP-1 cells, the expression of TNFα, IL-1β, and IL-6 on THP-1 cells, the expression of ICAM-1 and VCAM-1 on A549 cells which effect cell adhesion function. The suppression of those molecules is controlled by NF-κB and AP-1, which are activated by IκB and MAPK pathways. We also demonstract that GGS, Flos Lonicera, and chlorogenic acid induce the IL-10 secretion in LPS-induced RAW 264.7 cell lines.
Therefore, GGS protection activity against LPS-induced lung inflammatory mediators release and might be beneficial in the treatment of endotoxin-associated inflammation.

目錄
第一章 前言 1
第二章 文獻探討 4
（一）中醫文獻回顧 4
第一節 肺炎中醫病名的產生與沿革 4
第二節 肺炎病因病機 4
第三節 中醫對肺炎的分證及治療概論 5
第四節 銀翹散的文獻回顧 6
（二）現代醫學文獻回顧 9
第一節 內毒素及其產生的發炎反應 9
第二節 肺部發炎反應相關的細胞激素介紹 11
第三章 材料與方法
第一節 材料 18
1、實驗動物 18
2、感染原 18
3、試劑藥品 18
4、抗體 19
5、耗材 20
6、儀器 20
7、銀翹散的製備 21
第二節 方法
1、LPS誘發肺炎鼠之動物模式建立 23
2、支氣管肺泡沖洗液之細胞學檢測 24
3、組織染色之細胞觀察 25
4、Nitrite含量測定 25
5、ELISA分析 26
6、核蛋白分析 27
7、RNA分析 32
8、細胞培養及測量細胞生長及藥物毒性 34
9、銀翹散於高效液相層析之成份分析 35
10、THP-1單核細胞對 A549上皮細胞的附著力分析 36
11、流式細胞儀測定附著分子 37
12、統計方法 37


第四章 結果
第一部份 銀翹散對LPS誘發造成肺發炎老鼠模式保護作用及
免疫調節機制分析
第一節 不同濃度LPS造成肺部損傷的影響 38
第二節 銀翹散對LPS造成肺部損傷的影響 38
第三節 銀翹散對LPS造成肺部損傷產生的氣管內滲 42
出液之影響
第四節 銀翹散對LPS造成肺部損傷產生的肺泡沖洗 43
液中的血球量之影響
第五節　銀翹散對LPS誘發的趨化因子的影響 47
第六節 銀翹散對LPS誘發的發炎及抗發炎的細胞激素 49
之影響
第七節 銀翹散對LPS造成肺部損傷的肺泡沖洗液中的 51
一氧化氮及肺組織中的細胞激素誘發NO的合成
酵素之影響
第八節 銀翹散對LPS造成肺部損傷產生的肺組織中的 51
NF-κB及AP-1轉錄因子之影響

第二部分 銀翹散對LPS誘發鼠巨噬細胞細胞激素的影響
第一節 銀翹散及其組成之中藥對LPS誘發發炎鼠的 55
巨噬細胞生存率之影響
第二節 銀翹散及其組成之中藥對LPS 誘發發炎的細 58
胞激素TNFα之影響
第三節 銀翹散及其組成之中藥對LPS誘發抗發炎的 58
細胞激素IL-10之影響
第四節 銀翹散之高效液相層析分析 61 第五節 綠原酸對鼠巨噬細胞的IL-10分泌之影響 61
第六節 橙皮素對LPS、TNFα與IL-1β誘發人類似 61
巨噬細胞THP-1及人類肺部上皮細胞A549
之細胞激素分泌之影響
第七節 橙皮素對前發炎細胞激素誘發的細胞附著分 64
子之影響
第八節 橙皮素對LPS活化鼠肺組織及前發炎細胞激素 67
活化A549細胞株的NF-κB及AP-1之影響
第九節 橙皮素對TNFα誘發的IκB及MAPK路徑之影響 69
第五章 討論 71
第六章 結論 82
參考文獻 83
英文摘要 106
作者簡介 108

圖目錄
Figure 2.1 The cytokine network between the different cells. 13
Figure 4.1 the morphologic damage of lungs exposed to different concentration of LPS. 39
Figure 4.2 The lung morphology changes of GGS treatment. 40
Figure 4.3 The lung morphology changes of GGS, HBX and Hesperidin treatment. 41
Figure 4.4 The weight of lung and concentrations of proteins in BALF(I). 44
Figure 4.5 The weight of lung and concentrations of proteins in BALF(II). 45
Figure 4.6 The cell counts in the BALF. 46
Figure 4.7 The tatol cell counts and neutrophil number in the BALF. 48
Figure 4.8 Concentrations of the chemokines KC in the bronchoalveolar lavage fluid (BALF) and MIP-1 and MIP-2 in the lung tissue. 50
Figure 4.9 Concentrations of tumor necrosis factor-alpha (TNFα), interleukin (IL)-1β, IL-6, IL-4, IL-10, and IL-12 in the bronchoalveolar lavage fluid (BALF). 52
Figure 4.10 Concentrations of the nitrite/nitrate and iNOS. 54
Figure 4.11 GGS Reduces NF-κB and AP-1 activation. 56
Figure 4.12 GGS and its components effect the cell viability of mouse macrophage RAW 264.7 cell line. 57
Figure 4.13 Concentrations of tumor necrosis factor-alpha (TNFα) in mouse macrophage RAW 264.7. 59
Figure 4.14 Concentrations of IL-10 in mouse macrophage RAW 264.7. 60
Figure 4.15 HPLC chromatogram of the GGS.
62
Figure 4.16 Concentrations of IL-10 in mouse macrophage RAW 264.7. 63
Figure 4.17 Effect of HES on the expression of cytokine in lung epithelial cells A549 and macrophage-like cells THP-1. 65
Figure 4.18 HES reduces adhesion of THP-1 cells to A549 monolayers and Selective inhibition of TNF-α or IL-1β-stimulated ICAM-1 or VCAM-1 expression. 66
Figure 4.19 Hesperidin Reduces NF-κB and AP-1 activation in Lungs Exposed to Lipopolysaccharide and in A549 cells Exposed to proinflammatory cytokine. 68
Figure 4.20 Effect of HES on TNFα-induced IκB, ERK1/2, p38, or JNK activation in A549 epithelial cells. 70



表次

Table 3.1 Oligonucleotide primer designation for RT-PCR analysis 34
Table 3.2 The time and partition of solvent 36
Table 4.1 Effect of GGS on LPS-induced cytokines. 57

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