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研究生:余黃平
研究生(外文):Huang-Ping Yu
論文名稱:創傷性失血後之器官保護:性激素的角色與治療意義
論文名稱(外文):Maintenance of organ function following trauma-hemorrhage: Role of Sex Steroids
指導教授:樓迎統樓迎統引用關係
指導教授(外文):Ying-Tong Lau
學位類別:博士
校院名稱:長庚大學
系所名稱:臨床醫學研究所
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:2006
畢業學年度:94
語文別:英文
中文關鍵詞:創傷性失血器官保護性激素
外文關鍵詞:trauma-hemorrhageestrogensex steroidsestrogen receptor
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研究結果顯示,雄性激素抑制劑Flutamide可以改善創傷失血性休克所導致的心臟衰竭與小腸功能障礙。此外,Flutamide也被證實是藉由活化雌激素接受器(estrogen receptor)的途徑來達到上述的保護作用。而我們近期的研究也發現雌激素與β型雌激素接受器激動劑(estrogen receptor-β agonist)皆可以在創傷失血性休克方面扮演保護肺臟的角色。另外,我們也發現雌激素接受器阻斷劑(estrogen receptor antagonist)可以阻斷上述兩者的保護作用。因此可以證明雌激素與β型雌激素接受器激動劑皆是經由雌激素接受器的途徑達到肺臟的保護作用。基於上述發現,我們假設性荷爾蒙影響創傷失血性休克後的器官功能表現,並且雌激素接受器在維護創傷失血性休克後的器官功能方面扮演重要的角色。
雖然雌激素可以減輕心臟損傷,並且可以降低創傷失血性休克後引發的嗜中性球浸潤程度。但是雌激素究竟是經由何種亞型的雌激素接受器作用? 因此,本論文研究的目的如下:
1) 雌激素是經由那一亞型的雌激素接受器來達到創傷失血性休克的心臟保護作用? 是否與熱休克蛋白質有關?除了測量心臟功能外,心臟組織將被用於偵測熱休克蛋白質濃度與熱休克因子含量;
2) 雌激素是否在改善創傷失血性休克後的嗜中性球浸潤方面存在著組織類型與接受器的特殊性?為了回答上述問題肝臟、小腸與肺臟將被用來分析雌激素接受器α和β的表現程度、myeloperoxidase activity(嗜中性球浸潤程度的指標) 、cytokine-induced neutrophil chemoattractant (CINC)-1、CINC-3和intercellular adhesion molecule (ICAM)-1含量。
研究結果顯示,雌激素是經由β亞型的雌激素接受器來達到創傷失血性休克的心臟保護作用,並且與活化心臟熱休克蛋白質濃度與熱休克因子有關。此外,雌激素在改善創傷失血性休克後的嗜中性球浸潤方面存在著組織類型與接受器的特殊性,並且與肝臟、小腸與肺臟雌激素接受器α和β的表現程度相關。
A prolonged depression of cardiovascular, hepatocellular and intestinal functions occurs in male rats but not in proestrus females following trauma-hemorrhage and fluid resuscitation. Additionally, decreasing the androgen levels by prior castration or administering flutamide, an androgen antagonist, after trauma-hemorrhage in non-castrated males, significantly improves/maintains organ functions. Studies also implicate 17β-estradiol in the improvement/maintenance of organ functions following trauma-hemorrhage. Therefore, the presence of high estrogen or low androgen levels is critical for improving the outcome under those conditions.
Our studies have shown that administration of flutamide prevents the depression of myocardial function and attenuates intestinal injury following trauma-hemorrhage and resuscitation. Furthermore, the salutary effects of flutamide appear to be mediated via estrogen receptors. Our recent studies also implicate 17β-estradiol and estrogen receptor-β agonist in the attenuation of lung following trauma-hemorrhage. In addition, the findings that estrogen receptor antagonist, ICI 182,780 abolished 17β-estradiol and estrogen receptor-β agonist-induced attenuation of lung injury following trauma-hemorrhage, suggest that the salutary effects of 17β-estradiol and estrogen receptor-β agonist are mediated via estrogen receptor. Our hypothesis, therefore, is that sex hormones affect organ functions following trauma-hemorrhage; furthermore, estrogen receptors play a critical role for improving the outcome under those conditions.
Although 17β-estradiol administration after trauma-hemorrhage improves cardiac function and reduces tissue neutrophil sequestration in male rodents, it remains unknown which of the estrogen receptor subtypes mediates this effect. The specific aims are to: 1) evaluate which estrogen receptor is predominantly responsible for the salutary effects of 17β-estradiol on cardioprotection following trauma-hemorrhage and whether cardiac heat shock proteins (Hsps) are affected by 17β-estradiol administration under those conditions; cardiac output, stroke volume, and ±dP/dtmax were measured. In addition, heart tissues were collected for measurement of Hsps (32, 60, 70, and 90) and heat shock factor-1 (HSF-1) expressions; 2) determine whether the salutary effects of 17β-estradiol on attenuation of neutrophil accumulation following trauma-hemorrhage are tissue and receptor subtype specific; liver, small intestine, and lung were used for analysis of estrogen receptor-α and -β expression, myeloperoxidase activity (a marker of neutrophil infiltration), cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, and intercellular adhesion molecule (ICAM)-1 levels. One-way ANOVA and Tukey’s test were used for statistical analysis.
Cardiac output, stroke volume and ± dP/dtmax decreased significantly after trauma-hemorrhage, however, administration of estrogen receptor-β agonist diarylpropiolnitrile (DPN) after trauma-hemorrhage restored the above parameters. Moreover, DPN treatment prevented trauma-hemorrhage-mediated decrease in Hsp60 mRNA/protein and Hsp90 protein expressions in the heart. Hsp32 and Hsp70 mRNA/protein expression and HSF-1 DNA binding activity in the hearts were increased even above the shams in DPN treated hemorrhaged rats. In contrast, no significant change in the above parameters was observed in hemorrhaged rats treated with estrogen receptor-α agonist propyl pyrazole triol (PPT). Thus, the salutary effects of 17β-estradiol on cardiac function are mediated via estrogen receptor-β and estrogen receptor-β-induced up-regulation of Hsp likely plays a significant role in the 17β-estradiol-mediated cardioprotection after trauma-hemorrhage.
Furthermore, trauma-hemorrhage increased MPO activity, CINC-1, CINC-3, and ICAM-1 levels in the liver, intestine, and lung. These parameters were significantly improved in rats receiving 17β-estradiol after trauma-hemorrhage. Administration of the estrogen receptor-α agonist PPT but not the estrogen receptor-β agonist DPN improved the measured parameters in the liver. In contrast, DPN but not PPT significantly improved these parameters in the lung. In the intestine, estrogen receptor subtype specificity was not observed. Estrogen receptor-α mRNA expression was highest in the liver, whereas estrogen receptor-β mRNA expression was greatest in the lung. Thus, the salutary effects of 17β-estradiol administration on tissue neutrophil sequestration following trauma-hemorrhage are receptor subtype and tissue specific.
These studies should yield valuable new information concerning not only the role of sex steroid hormone-induced alterations in organ function, but also innovative approaches to improve organ function following trauma-hemorrhage in males.
CHAPTER I BACKGROUND/INTRODUCTION…………………………. 1
1. Trauma-hemorrhage and multiple organ failure……………….. 1
2. Gender dimorphism and trauma-hemorrhage……………………………….1
3. Role of sex steroids in trauma-hemorrhage…………………………………2
4. Synthesis of sex steroids…………………………………………………….3
5. Male sex steroids and trauma-hemorrhage……………………………….….4
6. Estrogen receptor and its signaling transduction……………………………..5
7. Effects of estrogen on estrogen receptor……………………………………6
8. Non-genomic pathway of estrogen…………………………………………..7
9. Non-genomic effects of estrogen…………………………………………….7
10. Genomic and non-genomic effects of sex steroids on trauma-hemorrhage…8
11. Cardioprotection of estrogen following trauma-hemorrhage………………..8
12. Role of heat shock proteins and heat shock factor-1 following injury……..9
13. Neutrophil accumulation after injury…………………………………….10
14. Salutary effects of estrogen on reduction of neutrophil infiltration following trauma-hemorrhage…………………………………………………………….11
15. Lung injury following trauma-hemorrhage………………………………...12
16. Role of nitric oxide in lung injury following hemorrhagic shock…………..13
CHAPTER II MATERIALS AND METHODS.….…………………………. 15
1. Model of Trauma-Hemorrhage and Resuscitation……………………………15
2. Sham-Operation Procedure…………………………………………………..16
3. Measurement of Cardiac Output and In Vivo Heart Performance…………...18
4. Isolation of Heart RNA………………………………….…………………..18
5. mRNA Expression Assay…………………………………………………….19
6. Western Blot Assay…………………………..………………………………19
7. Electrophoretic Mobility Shift Assay (EMSA)……….………………………20
8. Measurement of Myeloperoxidase (MPO) Activity………………………….20
9. Determination of CINC-1, CINC-3, and ICAM-1 Levels…………..………21
10. Preparation of Lung Tissue and Collection of Bronchoalveolar Fluid (BALF)………………………………………………………………….…22
11. Water Content Assay………………..……………………………………..24
12. Nitrate/Nitrite Assay………………………………………………………..24
13. IL-6 Assay……………………………..……………………………………25
14. Protein Assay in Lung Lavage……………..……………………………….25
15. Lactate Dehydrogenase Activity Assay……………………………………..25
CHAPTER III RESULTS.….….….….………………….……………………… 26
1. Effect of ER agonists on cardiovascular function
2. Effect of ER agonists on reduction of neutrophil accumulation
3. Effects of ER agonists on attenuation of lung injury
CHAPTER IV DISCUSSION…………………………………………………….33
CHAPTER V CONCLUSION.……………………………………………………46
REFERENCES…………………………………………………………….…………47
FIGURES AND TABLES………………………………………………..……..……69
LIST OF PUBLICATIONS ………………………………………………………….89
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1. 謝福助(2002),〈恐怖主義與反恐怖主義之難題〉,《淡江人文社會學刊》,第11期,頁127-154。
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3. 戴萬欽(2000),〈聯合國邁入廿一世紀—維持世界和平之挑戰與機會〉,《淡江人文社會學刊》,50週年校慶特刊,頁193-234。
4. 戴萬欽(2000),〈聯合國邁入廿一世紀—維持世界和平之挑戰與機會〉,《淡江人文社會學刊》,50週年校慶特刊,頁193-234。
5. 詹哲裕(1994),〈從民族主義的觀點論族群衝突之化解〉,《復興崗學報》,第51期,頁87-111。
6. 詹哲裕(1994),〈從民族主義的觀點論族群衝突之化解〉,《復興崗學報》,第51期,頁87-111。
7. 詹哲裕(1994),〈從民族主義的觀點論族群衝突之化解〉,《復興崗學報》,第51期,頁87-111。
8. 謝福助(2002),〈恐怖主義與反恐怖主義之難題〉,《淡江人文社會學刊》,第11期,頁127-154。
9. 謝福助(2002),〈恐怖主義與反恐怖主義之難題〉,《淡江人文社會學刊》,第11期,頁127-154。
10. 翁明賢(2003),〈國際恐怖主義與反恐行動的發展趨勢〉,《展望與探索》,第1期第6卷,頁1-5。
11. 翁明賢(2003),〈國際恐怖主義與反恐行動的發展趨勢〉,《展望與探索》,第1期第6卷,頁1-5。
12. 翁明賢(2003),〈國際恐怖主義與反恐行動的發展趨勢〉,《展望與探索》,第1期第6卷,頁1-5。
13. 南方朔(2003),〈當Jihad從抵抗變成聖戰〉,《新新聞週報》,第761期,頁110-113。
14. 南方朔(2003),〈當Jihad從抵抗變成聖戰〉,《新新聞週報》,第761期,頁110-113。
15. 南方朔(2003),〈當Jihad從抵抗變成聖戰〉,《新新聞週報》,第761期,頁110-113。