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系統識別號 U0026-0812200913590565
論文名稱(中文) 核轉錄因子Nrf2在缺血性休克及液體回輸中扮演的角色
論文名稱(英文) The Role of Nuclear Factor Erythroid 2–Related Factor 2 in Hemorrhagic Shock and Resuscitation
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 95
學期 2
出版年 96
研究生(中文) 陳昱豪
研究生(英文) Yu-hau Chen
電子信箱 s3694402@mail.ncku.edu.tw
學號 s3694402
學位類別 碩士
語文別 英文
論文頁數 73頁
口試委員 指導教授-莊季瑛
口試委員-黃阿敏
口試委員-蔡明哲
中文關鍵字 抗氧化反應單位  輸液回輸  缺血性休克 
英文關鍵字 fluid resuscitation  antioxidant response elements  Hemorrhagic shock 
學科別分類
中文摘要 急性缺血性休克會造成多重性器官衰竭且是意外傷害中主要的死因之一。液體的回輸是目前最常被使用在缺血性休克的急救。雖然在過去的研究中已經指出氧化壓力的產生是缺血性休克造成器官衰竭的主因,但在缺血性休克及輸液回輸後,其內生性的抗氧化系統的表現仍渾沌未明。Nrf2是一種轉錄調控因子,可以藉由與抗氧化反應單位(ARE)結合調控抗氧化基因的轉錄,其中包括了第一型血基質氧化酶循環酶(HO-1), γ-谷氨酰半胱氨酸合酶(γ-GCS)等。因此,在我們的研究中,將評估在缺血性休克及不同時間給予不同種類輸液後,分別對大腦、肝臟及肺臟的損傷狀況,並探討Nrf2活性及其下游蛋白HO-1及γ-GCS的表現。首先,我們藉由頸動脈的抽血使大鼠血壓在三十分鐘內下降至30-40毫米汞柱使缺血性休克發生 (hemorrhagic shock on set, HSOS),並令血壓維持在30-40毫米汞柱30分鐘,此時若不進行回輸液處理,大鼠將會死亡。由於我們的動物模式由頸動脈進行結紮抽血,此時伴隨著缺血性休克的發生,會造成抽血側全面性大腦半球缺血。我們發現缺血性休克自發生後五分鐘開始,會活化大腦Nrf2所調控的抗氧化系統且造成神經損傷。而缺血性休克發生後二十分鐘回輸輸液則有效地抑制了大腦中缺血性休克誘發的神經損傷、Nrf2的活化及HO-1的表現上升。但唯有回輸林格氏液混合全血(3:1)才能有效地抑制缺血性休克誘發大腦中的Nr2及γ-GCS蛋白質表現。然而在肝臟及肺臟中,缺血性休克並不影響Nrf2、γ-GCS及HO-1的蛋白質表現,但造成肝臟中Nrf2與DNA結合能力的雙相變化:早期的活化與晚期的抑制現象。此外,缺血性休克並不誘發周邊器官的受損,反之,回輸林格氏液混合全血卻造成肝臟及肺臟的嚴重傷害。相較於林格氏液混合全血,全血的回輸並不造成器官的傷害,這可能與其造成γ-GCS的上升以及抑制缺血性休克誘發肝臟中Nrf2活性及表現的雙相變化有關。我們亦發現HO-1的表現上升對於大腦及肝臟損傷是一靈敏的指標,然而全血回輸卻造成HO-1顯著性地下降。綜合這些結果顯示,缺血性休克及液體回輸對於組織損傷及Nrf2調控的抗氧化系統的影響具有器官上的個別差異:輸液回輸的時機對於大腦,以及輸液的種類對於肝臟及肺臟分別具有顯著的影響。我們的結果顯示延遲回輸全血是最好的治療缺血性休克的方式,因其除了可以避免造成的大腦損傷也不會誘發周邊組織的傷害。最後,Nrf2的活化在缺血性休克中是否能提供保護的功能,仍須以外加Nrf2活化劑的實驗進一步加以釐清。
英文摘要 Acute hemorrhagic shock (HS) causes multiple organs failure and is one of the leading causes of death in accidents. Fluid resuscitation is the most considerable treatment for HS. Although oxidative stress and inflammatory responses has been reported as the causality of HS-induced multiple organs failure, the manifestation of endogenous antioxidant system in response to HS and resuscitation is still unclear. Nuclear factor-erythroid 2 -related factor 2 (Nrf2) is a transcriptional factor binding to the antioxidant response elements (AREs) to regulate the transcription of antioxidant genes, including heme oxygenase 1 (HO-1), and γ-glutamycsteine synthetase (γ-GCS). Therefore, our study attempts to investigate the Nrf2 DNA binding activity and HO-1 and γ-GCS protein expression in brain, lung and liver after HS and resuscitation. We induced acute HS on set (HSOS) by blood withdrawing from rat right common carotid artery within 30 minutes and maintained the mean arterial pressure in 30-40 mmHg for another 30 minutes of HS period. Moreover, our model also induced global cerebral ischemia due to the unilateral common carotid artery occlusion for blood withdrawal and hemorrhagic hypotension. We found that in brain, hemorrhagic shock activated Nrf2-regulated antioxidant system and caused neuronal loss as early as 5 minutes after HSOS. Fluid resuscitation at 20 minutes after HSOS significantly prevented HS-induced neuronal loss, Nrf2 activation, and HO-1 upregulation. Resuscitation with mixture of L-isomer lactate Ringer’ solution and shed blood (3:1) (LR+BL) statistically inhibited HS-increased Nrf2 and γ-GCS protein expression but not shed blood (BL) in brain. In livers and lungs, however, HS did not modulate Nrf2, γ-GCS, and HO-1 protein expression, except a biphasic change of Nrf2 DNA binding activity: an early activation and late inhibition in liver. Moreover, HS did not induce organ damage, whereas resuscitation with LR+BL caused liver and lung injuries. In comparison with LR+BL, resuscitation with BL did not cause tissue damage and that was correlated to γ-GCS upregulation and the reverse of HS-induced biphasic change of Nrf2 activity and protein expression. We also found that HO-1 upregulation was a sensitive response to brain and liver damage, however, a specific HO-1 downregulation in lung after BL resuscitation. These results indicated that the effect of HS and fluid resuscitation on tissue damage and Nrf2-regulated antioxidant system was organ specific, resuscitation time-dependent in brain, and resuscitation fluid-dependent in livers and lungs. Our results suggested that late resuscitation with BL has potential in the prevention of HS-induced brain injury without inducing peripheral organ damage. However, the role of Nrf2 activation after HS on tissue protection has to be further confirmed by exogenous administration of Nrf2 inducers.
論文目次 Abstract..................................................i
Chinese...................................................i
English.................................................iii
Acknowledgments...........................................v
Table of Contents........................................vi
Index to Tables.........................................vii
Index to Figures.......................................viii
Introduction..............................................1
Rationales & Hypothesis..................................9
Specific aims............................................10
Materials and Methods....................................11
Results..................................................18
Discussion...............................................24
References...............................................32
Appendix.................................................62
About the Author.........................................64
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