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研究生:李政翰
研究生(外文):Cheng-Han Lee
論文名稱:熱休克前處理在高濃度氧氣引起新生大鼠之肺損傷的角色探討
論文名稱(外文):The role of heat shock pretreatment in hyperoxia-induced lung injury in neonatal rats
指導教授:許勤許勤引用關係楊瑞成楊瑞成引用關係
指導教授(外文):Chin HsuRei-Cheng Yang
口試委員:陳秀玲鍾美勇
口試委員(外文):Hsiu-Lin ChenMei-Yung Chung
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:醫學研究所碩士班
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:2018
畢業學年度:106
語文別:中文
論文頁數:69
中文關鍵詞:熱休克蛋白肺損傷高氧
外文關鍵詞:heat shock proteinlung injuryhyperoxia
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隨著早產兒重症加護照顧之進步,早產兒的存活率在過去 40 年間有顯著的進步,但其出生後急性肺損傷引起之肺支氣管發育不良的發生率仍居高不下,往往造成社會及家庭嚴重的負擔。肺支氣管發育不良屬於肺部慢性發炎造成的疾病,常見於使用高濃度氧氣的早產兒。研究指出高濃度的氧氣會促使發炎細胞激素增加,進而吸引嗜中性白血球與巨噬細胞進入肺泡組織,引發肺臟局部性發炎反應而造成傷害甚至細胞凋亡。
學者研究已明確指出熱休克蛋白具有細胞保護作用,且可以抑制細胞凋亡。目前有關熱休克蛋白保護高濃度氧氣造成的肺上皮細胞損傷的機制仍未定論,且尚無應用在防止早產兒因使用高濃度氧氣造成 BPD 的臨床治療。因此為了瞭解熱休克蛋白在高濃度氧氣引起新生大鼠之肺損傷的角色,我們利用新生大鼠探討了熱休克蛋白70(HSP70)高氧誘導的肺損傷的作用。實驗時使用懷孕的Wistar大鼠。新生幼崽在妊娠期自然足月出生,然後匯集,隨機分為4組: 完全沒有處置之後生活在一般大氣狀況的控制組(Control)、接受熱休克前處置後生活在一般大氣組(Heat shock with Room air) 、完全沒有處置之後生活在高濃度氧氣狀況組(Hyperoxia)以及接受熱休克前處置後生活在高濃度氧氣組(Heat shock with Hyperoxia)。熱休克處理利用電毯加熱至核心體溫為42℃,持續15分鐘。高濃度氧氣狀況組(Hyperoxia)以及接受熱休克前處置後生活在高濃度氧氣組(Heat shock with Hyperoxia)這2組新生大鼠均暴露於高濃度氧氣(氧氣濃度90%)的環境。在高濃度氧氣暴露的第3,7,14和21日犧牲新生大鼠,然後收集血液,支氣管肺泡灌洗液(BALF)和肺組織用於分析。結果發現與單純暴露於高濃度氧氣的新生鼠相比,接受熱休克前處理新生鼠在高濃度氧氣暴露期間其存活率有顯著提高(p <0.05)。支氣管肺泡灌洗液中的嗜中性球細胞數在接受熱休克前處理並暴露在高濃度氧氣這一組有顯著降低(p <0.05)。另外,在21天大時比較肺部組織的病理變化發現在單純暴露高濃度氧氧組中有較大的肺泡,較少的肺泡數量,以及更加增厚的纖維隔膜形成。因此我們得出了結論,熱休克前處理誘導熱休克蛋白產生,在高濃度氧氣的環境下顯著增加新生大鼠的生存率,以及減少了肺部病理損傷。這些結果表明,利用熱休克蛋白治療高濃度氧氣所誘導的肺損傷可能降低肺部發展為肺支氣管發育不全的風險。
With the improvement of neonatal intensive care, the survival rate of premature infants has significant increased over the past 40 years, however, the incidence of bronchopulmoary dysplasia (BPD) in survival infants is still high, resulting in large financial burdens on the society and families. BPD is a pulmonary fibrotic change from chronic inflammatory injury. Exposure to high concentration of oxygen is thought to play a significant role in the pathogenesis of lung injury in premature infants. The damage of BPD is mainly caused by hyperoxia, which leads to the injury of pulmonary epithelial cell via apoptosis and enhance the gene expression of inflammatory cytokines and contributes to the infiltration of inflammatory cells into alveolar cells. For decades, heat shock protein(HSP) has been well demonstrated to act as molecular chaperones to against reactive oxygen species(ROS) induced cell stress by helping in the refolding of misfolded proteins and assisting in eliminating irreversible cell damage. However, the effect of heat shock protein in protecting hyperoxia-induced apoptotic lung epithelial cells is still unclear. So far, there is no appropriate approach to prevent the occurrence of BPD in premature infants by the highly conserved cellular self-protective phenomenon. Therefore, this study aimed to investigate the effect of heat shock response in hyperoxia-induced BPD in neonatal rats and to assess its therapeutic potential.
In this study, timed pregnant Wistar rats were obtained. Neonatal pups were delivered naturally at term gestation, and then pooled, randomly assigned into two groups to receive heat stimulation (core temperature at 42℃, for 15 minutes) or room temperature respectively. All newborn rats were placed in hyperoxia (Oxygen concentration 90%). The newborn rats were sacrificed at Day 3,7,14 and 21 of exposure, and then the blood, bronchoalveolar lavage fluid (BALF) and lung tissue were collected for analysis. The results showed that the survival rates in the heat-hyperoxia group were improved compared with the hyperoxia group (p<0.05). The cell numbers in bronchoalveolar lavage fluid were significantly decreased in the heat-hyperoxia group (p<0.05). In addition, more enlarged alveoli and more thickening fibrous septa formation were founded in hyperoxia group.
We concluded that HSP70 induced by heat shock pretreatment, significantly increased survival rate and reduced lung pathological injury in hyperoxia environment. These results suggest that treatment of hyperoxia-induced lung injury with heat shock protein might reduce the risk of developing BPD.
中文摘要-------------------------------------2-3
英文摘要-------------------------------------4-6
致謝詞---------------------------------------8
研究背景-------------------------------------9-23
研究方法與材料-------------------------------24-34
結果-----------------------------------------35-38
圖表-----------------------------------------39-50
討論-----------------------------------------50-58
結論-----------------------------------------59
參考文獻-------------------------------------60-69
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