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系統識別號 U0026-2406201110522900
論文名稱(中文) 低溫療法及右美沙芬於熱中風大白鼠相關肺損傷之保護效果
論文名稱(英文) Both Hypothermia and Dextromethorphan Protect Against Acute Lung Injury in Experimental Heatstroke
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 99
學期 2
出版年 100
研究生(中文) 楊煦星
研究生(英文) Hsi-Hsing Yang
學號 s5894124
學位類別 博士
語文別 中文
論文頁數 108頁
口試委員 指導教授-鄭瑞棠
口試委員-林茂村
召集委員-吳昭良
口試委員-薛尊仁
口試委員-高尚志
中文關鍵字 急性肺損傷  熱中風  低溫療法  右美沙芬 
英文關鍵字 Acute lung injury  Heatstroke  Hypothermia  Dextromethorphan 
學科別分類
中文摘要 呼吸系統,對人類生存來說,是最重要的器官系統之一。急性肺損傷為一種急性和持續性的肺部發炎,合併有血管滲透性增加之症候群。因為全球暖化氣候變遷引起熱浪頻繁,已使熱中風之威脅逐年增加。在嚴重的熱中風病例裡會發展成急性肺損傷或者急性呼吸窘迫症候群,其死亡率可超過50%。然而,目前投注於熱中風相關之急性肺損傷動物研究,卻付之闕如。在本研究中,我們將透過實驗動物,探索熱中風相關急性肺損傷之潛力性的治療方式,並且探討其可能機轉。以往對於低溫療法保護熱中風,在臨床上其被接受的解釋為,快速冷卻降低代謝率而減少能源耗損。不過,是否在低溫治療對保護熱中風裡有其他機轉,特別是低溫治療對呼吸系統的影響,目前仍不清楚。因此,我們具體目標之一是確定低溫治療(全身低溫療法,或是選擇性的腦部低溫療法)是否能透過改善急性肺損傷,而保護熱中風,並提升其生存活。
實驗之方法乃以大白鼠,經加熱墊加熱至43℃,平均68分鐘後誘發熱中風,然後將其恢復於室溫下。結果顯示在熱中風期間發生之急性肺發炎和損傷及酸鹼不平衡和低血氧,可透過全身低溫療法而改善。另一群動物研究的結果揭示,以逆行性頸靜脈灌注4°C生理食鹽水之腦部低溫療法,可明顯降低由熱引致之急性肺損傷的嚴重度。在我們的實驗熱中風大白鼠,其肺灌洗液中,谷氨酸濃度上昇,而新近的研究也顯示在高濃度氧氣下,可透過內生的谷氨酸濃度上昇,再經由N-甲基D-天冬氨酸接受器(NMDAR)引發幼鼠肺損傷。右美沙芬(Dextromethorphan),作為NMDA接受器拮抗劑,且有抗氧化劑的特性。因此,這項研究的另一個具體的目的是去測試右美沙芬對熱中風相關之急性肺損傷的影響。結果顯示,熱中風大白鼠經右美沙芬治療後,明顯降低肺灌洗液之促發炎細胞激素、骨髓過氧化酶活性、谷氨酸濃度、乳酸-丙酮酸比率、總蛋白質和乳酸脫氫酵素濃度,同時明顯提升抗發炎細胞激素Interleukin-10 (IL-10)。熱中風大白鼠經右美沙芬治療後,也顯著改善肺組織損害、延長存活時間、並且改進其生理參數。
總結上述結果,我們發現在熱中風後立即給予低溫療法,或者右美沙芬治療,可以透過改善肺發炎和肺損傷,而有效地保護熱中風。
英文摘要 For human survival, one of the most important organ systems is respiratory system. Acute lung injury (ALI) is defined as a syndrome of acute and persistent lung inflammation with increased vascular permeability. The threat of heatstroke is increasing because of global climate warming that results in heat waves. ALI or Acute respiratory distress syndrome (ARDS) develops in severe heatstroke cases and the mortality rate can be more than 50%. However, there was a lack of animal studies focusing on the heatstroke-related acute lung injury. In this study, we explored potential treatments and discussed the possible mechanisms for heatstroke-related acute lung injury in the experimental model. The decreased metabolic rate during rapid cooling and the ensuing decreased expenditure of energy substrates have been an accepted explanation for hypothermic protection in heatstroke patients. However, whether there are other mechanisms for hypothermic protection in heatstroke, especially the impact on respiratory system, remains unclear. Therefore, one of our specific aims was to determine whether hypothermia (whole body cooling or selective brain cooling) could protect against heatstroke and improve survival time by attenuating acute lung inflammation and injury.
Induction of heatstroke in Sprague-Dawley rats by using temperature-controlled heating pads set at 430C was achieved after the average time of 68 minutes. The results showed that acute lung inflammation and injury, acid-base imbalance, and hypoxia that occurred during heatstroke were significantly improved by treatment with whole body cooling. Additionally, the results of another set of animal studies revealed that brain cooling caused by 4°C saline infusion via retrograde jugular vein significantly reduced the severity of heat-induced acute lung injury. The levels of glutamate in the Bronchoalveolar lavage fluid increased obviously in our experimental model of heatstroke. Recent research shows that the endogenous glutamate mediated lung damage induced by hyperoxia through N-methyl-D-aspartate receptor (NMDAR) in newborn rats. Dextromethorphan (DM) acts as a NMDAR antagonist and it also has the properties of antioxidant. So, another specific aim of this study was to test the effects of dextromethorphan on heatstroke-related acute lung injury. The results showed that inflammatory cytokines, myeloperoxidase activity, glutamate, lactate/pyruvate ratio, total protein, and LDH levels in bronchoalveolar lavage fluids (BALFs) were significantly reduced and anti-inflammatory cytokine IL-10 levels in BAL were found significantly elevated in heatstroke rats after DM treatment. DM also significantly ameliorated lung tissue damage as measured by histological examination, prolonged the survival time, and improved physiological parameters of heatstroke.
We concluded that using either hypothermia or DM therapies immediately after the onset of heatstroke is effective in protecting against heatstroke by attenuating acute lung inflammation and lung injury
論文目次 Table of Contents
Chinese Abstract I
Abstract IV
Acknowledgements VII
Table of Contents VIII
List of Figures XI
Abbreviations XIV

Chapter One:
Introduction 1
1.1 Acute lung injury 2
1.2 Pathophysiology of acute lung injury 3
1.3 Current treatments for acute lung injury 4
1.4 Heatstroke 5
1.5 Heatstroke related acute lung injury 7
1.6 Hypothermia for acute lung jury 8
1.7 Roles of glutamate and N-methyl-D-asparate receptor in acute lung injury 9
1.8 Research goals 10

Chapter Two:
Materials and Methods 12
2.1 Experimental Animals 13
2.2 Surgery and Physiologic Parameter Monitoring 13
2.3 Induction of Heatstroke 13
2.4 Bronchoalveolar lavage 14
2.5 Measurement of Cerebral Blood Flow and Brain Temperature 14
2.6 Measurement of Arterial Blood Gas 15
2.7 Measurement of Cytokines 15
2.8 Measurement of Glutamate and Lactate/Pyruvate ratio 15
2.9 Measurement of Nitric Oxide Metabolites 16
2.10 Measurement of Exudates volume and amounts of PMN cells 16
2.11 Determination of MPO Activity 17
2.12 Determination of Lactate dehydrogenase activity 17
2.13 Determination of BAL total protein 17
2.14 Determination of Acute Lung Damage Score 17
2.15 Assessment of Inducible Nitric Oxide Synthase in the Lung 18
2.16 Statistics 19
Chapter Three:
Attenuation of Acute Lung Inflammation and Injury by Whole Body Cooling in a Rat Heatstroke Model 20
3.1 Abstract 21
3.2 Introduction 22
3.3 Results 23
3.4 Discussion 24
Chapter Four:
Inhibition of Acute Lung Inflammation and Injury Is a Target of Brain Cooling after Heatstroke Injury 41
4.1 Abstract 42
4.2 Introduction 44
4.3 Results 45
4.4 Discussion 47
Chapter Five:
Attenuation of Acute Lung Inflammation and Injury during Experimental Heatstroke by Dextromethorphan 61
5.1 Abstract 62
5.2 Introduction 64
5.3 Results 66
5.4 Discussion 69

Chapter Six:
Conclusions and further directions 88
References 91
Bibliography 102
Appendixes 108
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