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研究生:趙貞如
研究生(外文):Chao,Chen-Ju
論文名稱:探討Dextromethorphan對內毒素誘發肺損傷之保護作用
論文名稱(外文):The protective effect of dextromethorphan on lipopolysaccharide-induced lung injury in rats.
指導教授:張宏張宏引用關係周志中
指導教授(外文):Chang, HungChou, Tz-Chong
口試委員:王家儀高毓儒吳清平
口試委員(外文):Wang, Jia-YiKou, Yu-RuWu, Chin-Pyng
口試日期:2012-05-24
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:83
中文關鍵詞:肺損傷內質網壓力
外文關鍵詞:lung injuryER stress
相關次數:
  • 被引用被引用:0
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  • 下載下載:3
  • 收藏至我的研究室書目清單書目收藏:0
急性肺損傷 (acute lung injury, ALI) 為臨床上常見嚴重急症,有極高的死亡率。當肺泡受到感染時,嗜中性白血球會大量遷移到肺部組織,毒殺外來物質,但發炎物質亦會傷害肺臟組織,嚴重時會造成急性呼吸窘迫症候群 (acute respiratory distress syndrome, ARDS) 致死。研究指出,急性肺損傷病患的體內往往承受著過多的發炎物質及氧化壓力。因此,降低發炎反應及氧化壓力是治療急性肺損傷的ㄧ個有利方向。 Dextromethorphan 是 NMDA 接受器的抑制劑,在臨床上是已使用多年的治療咳嗽藥物,文獻中指出, Dextromethorphan 具有抗發炎和抗氧化的功效。本研究目的主要在探討內毒素誘發肺損傷模式中,評估給予 Dextromethorphan 是否有保護效果並探討相關機制。本實驗設計為於實驗前一小時投予 Dextromethorphan (20 mg/kg, i.p.) ,之後再於氣管內滴入內毒素 (5 mg/kg),並,在第 6小時將動物犧牲及評估肺損傷程度。實驗結果顯示, Dextromethorphan 可顯著減少支氣管肺泡灌洗液中蛋白質濃度、白血球數目、細胞激素 (tumor necrosis factors-α, TNF-α;intreleukine-1β, IL-1β;intreleukine-6, IL-6) 及趨化激素 (macrophage inflammatory, MIP-2) ,且可減少肺組織中肺組織濕/乾重量比、骨髓過氧化酶 (myeloperoxidase, MPO) 活性,並降低 COX-2 和 iNOS 蛋白質表現量。同時,也明顯改善肺臟病理組織變化。此外,本實驗也發現 Dextromethorphan 顯著減少肺組織中 NF-κB 表現量。因此,我們推論 Dextromethorphan 可能是經由減少細胞激素、趨化激素釋放與降低發炎性基因表現及自由基生成以及降低 NF-κB 的轉錄作用,同時 Dextromethorphan 也可減少肺組織中 ROS 和 NO 含量及抑制肺組織 iNOS、 XBP1、 ASK1、 p38、 CHOP 和 caspase-3 等表現,但可增加 HO-1 和 GRP78 ,降低細胞走向細胞凋亡路徑。因此,推論Dextromethorphan 藉由減少細胞激素、趨化激素釋放與降低發炎性基因表現及自由基生成,使內質網壓力相關因子及細胞凋亡被抑制,而達到改善內毒素誘發肺損傷。

The characterization of acute lung injury (ALI) includes impairment of the alveolar-capillary barrier, and accumulation of protein rich fluid and influx of inflammatory cells into the alveolar airspace, and dysfunction of lung which are associated with pulmonary cell damage. Dextromethorphan (DM), a noncompetitive N-methyl-D-aspartate receptor antagonist, exerts an effect in endotoxemia rats. However, whether DM has a beneficial effect on lipopolysaccharide (LPS)-induced ALI is unreported. The aim of this study was to investigate the effects of DM on LPS-induced lung injury, and further elucidated the mechanisms involved. Rats were given intraperitioneal injection of DM (20 mg/kg) 1 h before intratracheally injection of LPS (5 mg/kg). Our results found that DM significantly attenuated the symptoms of ALI, reflected by attenuation of Wet/dry ratio of the lungs, protein concentration and number of total WBC counts in bronchoalveolar lavage fluid (BALF) accompanied by attenuation of lung pathological changes. Meanwhile, DM significantly inhibited myeloperoxidase activity and the levels of superoxide and nitrite/nimate in lung tissue, and alleviated LPS-induced the production of TNF-α, IL-6, IL-1β, MIP-2 in BALF, as well as COX-2 and iNOS expression. Furthermore, the increased nuclear tanslocation of NF-κB p65, ROS, iNOS formation and endoplasmic reticulum stress (ER stress) in ALI significantly-related marker such as XBP1, ASK1, p38, CHOP, interestingly, DM upregulated HO-1 and GRP78 expression in lung tissue accompanied by reduced apoptosis. In conclusion, we demonstrate for the
first time that treatment with DM exerts a beneficial effect in LPS-induced lung injury through decrease of proinflammatory mediators formation, NF-κB a function and ER stress subsequently leading to attenuation of inflammation and apoptosis.


目錄-----------------------------------------------------Ⅰ
圖目錄---------------------------------------------------Ⅱ
中文摘要-------------------------------------------------Ⅳ
英文摘要-------------------------------------------------Ⅵ
第一章 緒論---------------------------------------------- 1
第二章 研究目的------------------------------------------18
第三章 材料與方法----------------------------------------19
第四章 實驗結果------------------------------------------38
第五章 討論----------------------------------------------48
第六章 總結----------------------------------------------59
圖次-----------------------------------------------------61
參考資料-------------------------------------------------84

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