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研究生:龔育千
研究生(外文):Yu-Chien Kung
論文名稱:探討硫辛酸對內毒素合併呼吸器誘發肺損傷之保護影響
論文名稱(外文):The protective effect of alpha-lipoic acid on ventilator and 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):Hung ChangTz-Chong Chou
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:2010
畢業學年度:98
語文別:中文
論文頁數:110
中文關鍵詞:硫辛酸呼吸器誘發肺損傷
外文關鍵詞:alpha-lipoic acidVentilator-induced Lung Injury
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呼吸器常用於呼吸衰竭的病人,若不適當使用或長時間給予呼吸器,皆易造成肺部損傷,並引發大量發炎物質的釋放,稱之呼吸器誘發肺損傷 (Ventilator-induced Lung Injury, VILI)。過去已有文獻指出,單獨給予低中度潮氣容積並不會導致肺損傷,但如合併一些刺激物質如:內毒素、油酸、鹽酸等,則會誘發肺部損傷,故本研究主要模擬臨床上有肺部疾病的病人長時間給予呼吸器且合併有感染發炎情況下所造成的肺損傷之動物模式下行一系列研究。以往研究已發現,在此呼吸器誘發肺損傷動物模式中會增加自由基生成,進而造成肺組織傷害。因此,或許可藉由使用具降低氧化壓力之藥物以改善肺損傷情形。硫辛酸 (α-lipoic acid, ALA) 是一種存在於粒線體的輔酶,具有多種細胞保護作用,可明顯改善氧化壓力所造成的相關疾病。本研究目的主要在探討內毒素合併呼吸器所誘導肺損傷模式中,評估給予硫辛酸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硫辛酸 (25,50,100 mg/kg, i.p.),之後再於氣管內滴入內毒素 (2 mg/kg),並設定潮氣容積 (VT):20 ml/kg,每分鐘60次呼吸次數,在第3小時將動物犧牲及評估肺損傷程度。 實驗結果顯示,硫辛酸 (100 mg/kg) 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、丙二醛 (Malondialdehyde, MDA) 生成量,並降低COX-2蛋白質表現量。同時,也明顯改善肺臟病理組織變化。此外,本實驗也發現硫辛酸 (100 mg/kg) 顯著減少肺組織中超氧游離基 (O2·–) 含量及抑制肺組織iNOS、XBP1、ASK1、p38、CHOP等表現,但可增加HO-1和GRP78基因表現量,導致caspase-3蛋白質表現量減少,降低細胞走向細胞凋亡路徑。因此,我們推論硫辛酸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,使內質網壓力相關因子及細胞凋亡被抑制但增加HO-1及GRP78基因表現,而達到預防呼吸器誘發肺損傷的療效。
Mechanical ventilation (MV) is an important therapeutic technique for patients with respiratory failure. However, an inappropriate or long time tidal volume used may cause lung injury, which may be the consequence of inflammatory response to mechanical ventilation, named ventilator-induced lung injury (VILI). Previous reports have demonstrated that MV alone with low and moderate tidal volume, may not cause lung injury. However, when ventilator combined with various pro-inflammatory compounds, including lipopolysaccharide (LPS), hydrochloric acid or oleic acid, the VILI may occur. Additionally, there were several studies indicate that increased free radical formation play a critical role in the pathogenesis of VILI. Therefore, reducing reactive oxygen species (ROS) may ameliorate the damage of the lung tissues. Alpha-lipoic acid (ALA), a naturally occurring antioxidant and a cofactor of mitochondrial respiratory enzyme, was reported to improve various diseases with high oxidative stress. The aim of this study was to investigate the effect of ALA on ventilator and LPS-induced lung injury, and further elucidated the mechanisms involved. In this study, the VILI model was established by using as intratracheal instillation of LPS (2 mg/kg) followed by VT=20 ml/kg at 60 breaths per min in rats. Rats were pretreated with ALA (25-100 mg/kg, i.p.) one hour before treatment with LPS and MV, and rat were sacrificed at 3 hours after LPS and MV treatment. ALA (100 mg/kg) significantly reduced protein concentration, total cell count, and TNF-α, IL-6, IL-1β, and MIP-2 levels in bronchoalveolar lavage fluid (BALF). Wet/dry ratio, myeloperoxidase (MPO) activity, malondialdehyde (MDA), and COX-2 protein expression in lung, accompanied by significantly improvement of the pathological changes of lung tissue. In addition, ALA (100 mg/kg) significantly diminished superoxide (O2·–) formation and inhibited iNOS, XBP1, ASK1, p38, CHOP, caspase-3 gene expression but upregulated HO-1, GRP78 expression in lung tissue, accompanied by reduced apoptosis. In conclusion, we demonstrate for the first time that treatment with ALA (100 mg/kg) exerts a beneficial effect in ventilator and LPS-induced lung injury through decrease of proinflammatory mediators formation, but enhancement of HO-1 and GRP78 gene expression, subsequently leading to attenuation of apoptosis.
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中文摘要----------------------------------------------------------------------------------IV

英文摘要---------------------------------------------------------------------------VI

英文縮寫對照表----------------------------------------------------------------------VIII

緒論----------------------------------------------------------------------------1
研究目的-----------------------------------------------------------------------------21
材料與方法--------------------------------------------------------------------------22
實驗結果-----------------------------------------------------------------------------40
討論------------------------------------------------------------------------------------49
結論------------------------------------------------------------------------------------61
圖次----------------------------------------------------------------------------------------63

參考文獻----------------------------------------------------------------------------------85
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