中文摘要

近日在全地引起的新興疾病諸如中東呼吸症候群(middle east respiratory syndrome, MERS)、急性呼吸道症候群(severe acute respiratory syndrome, SARS)以及伊波拉病毒、炭疽桿菌和退伍軍人桿菌等引起的高死亡率，均與肺部的發炎、肺部的水腫相關。其發病機轉除了與微生物感染有關外，肺部的嚴重發炎反應也扮演極重要的角色。肺部的炎症可因發炎細胞滯留在肺內，引起肺內氧化壓力的上升、肺循環壓力上升及肺微血管通透性的增加。此外血球滯留在肺內引起的肺組織缺血或再灌流，也有一定的關係。腸道的壞死、胰臟的發炎也會引起全身性的發炎反應，進而引起肺臟的血流動力學的改變，肺微血管的通透性增加，緊接著引發肺水腫的現象。在初步研究中發現，當肺組織在缺血再灌流的環境下，肺內的積水上升(p < 0.01)、肺組織灌洗液中蛋白質(PCBAL)含量上升(p < 0.001)及肺微血管通透性上升(p < 0.05)。使用了水溶性的氧自由基吞噬劑(dimethylthiourea)後損傷的參數均明顯改善(PCBAL, p < 0.01; 肺重/體重比(LW/BW)，p < 0.05)，而大分子量的自由基吞噬劑superoxide dismutase以及catalase就未呈現有保護作用(p > 0.05)，此可能與這兩者的蛋白質分子量太大無法進入細胞內有關。在另一組實驗中，我們證實當胰臟在缺血再灌流引發之胰臟發炎後，呼吸道的反應性會上升(p < 0.001)。此反應性的上升應該與發炎反應、肺內白血球的上升以及腫瘤壞死因子、羥自由基、氮化壓力上升有關。使用抗氧化劑薑黃素後，這些反應均明顯減少。由於胰臟缺血再灌流後血中澱粉酶、脂肪酶及蛋白酶的上升間接證明是因胰液外滲到血液中(p < 0.01)，進而進入肺內引發肺部的發炎甚至水腫。因此在進一步的研究中，我們建立了以胰液直接噴灑至實驗大鼠呼吸道的實驗模式。在實驗中證實胰液會引發阻塞性及限制性肺部功能變化，此與肺部發炎性反應有關。此外，引發肺微血管通透性病變，血液中白血球數量上升、紅血球數量降低。此外，血紅素、血球容積比、平均紅血球容積、平均紅血球血紅素重量、平均紅血球血紅素濃度等均上升，並且使血小板數值下降，進而造成瀰漫性血管凝血現象。在血清與肺組織灌洗液中均發現乳酸脫氫酶(lactate dehydrogenase, LDH)上升，顯示細胞損傷嚴重。在使用全套肺功能相關生理試驗(pulmonary function test, PFT)發現最大自發性換氣量、中間潮氣呼氣流量、阻力指數、肺活量、呼吸功、最大呼氣流速、最大中段吐氣流量及用力吐氣時間在50%的氣體流量均下降，而肺總量、肺餘容積和肺順應性(chord compliance)則是上升，顯示出肺功能因此受到影響。使用薑黃素後對於實驗大鼠的支氣管灌洗液(bronchoalveolar lavage fluid, BALF)中的蛋白質、血清中的氮化壓力、氧化壓力、乳酸脫氫酶以及肺功能參數，均顯示具有明顯的保護效用。透過本研究證實薑黃素具備強力的抗氧化能力，可減少氧化壓力及氮化壓力，以致無論在缺血再灌流或是胰液引發的肺損傷及肺功能改變，均能產生明顯的改善效果。此外本研究也建立了一個以霧化胰液至肺內引發肺損傷的實驗模式，對於胰臟發炎及肺部病變提供了一個很好的實驗模式。

Abstract

Emerging diseases such as middle east respiratory syndrome, severe acute respiratory syndrome or other infections induced by Ebola virus, Bacillus anthracis, and Legionnaire’s disease which are all related to lung inflammation and lung edema with high mortality. The mechanisms involved in these emerging diseases could be related to the microbes infection and the inflammation reactions involved in the lung. The inflammation of the lung could be induced by sequestered of the inflammatory cells in the lung, so that oxidative stress increased, pulmonary arterial pressure increased, and the permeability changes in pulmonary capillaries. Besides, blood cells sequestered in the lung-induced ischemia/ reperfusion (I/R) of lung tissues are also related. Necrosis of intestines or inflammation of pancreas also could induce systemic inflammatory responses, so that hemodynamic changes in the lung, pulmonary capillary permeability changes and lung edema ensured.
In the pilot study we proved that ischemia/ reperfusion of the lung tissues induced lung water increase (p < 0.01), lavage protein in pulmonary capillary bronchial alveolar lavage (PCBAL) increase (p < 0.001) and the permeability coefficient of pulmonary capillary increase (p < 0.05). After administration of water soluble oxygen radical scavenger, dimethylthiourea, the lung injury parameters attenuated significantly (PCBAL, p < 0.01; LW/BW, p < 0.05). However, big molecules of oxygen radical scavengers such as superoxide dismutase and catalase did not prove with protective effects (p > 0.05). These could be related to the big molecules of superoxide dismutase and catalase which can’t penetrate into cells.
Further experiment, we demonstrated that ischemia/ reperfusion of pancreas induced inflammation of pancreas and the elevation of airways reactivity which could be related to the I/R of pancreas-induced increase of inflammation white cell, tumor necrotic factor, hydroxyl radicals, and nitrosative stress. After administration of curcumin (antioxidant), all these responses are attenuated. Since post I/R of pancreas induced increase of amylase, lipase, protease in the blood, it proved indirectly that pancreatic juice exudates into the blood (p < 0.01), so that intrapulmonary inflammation and lung edema.
In this study we set up the model by aerosolized of pancreatic juice and infused the aerosol directly into airway. We demonstrated that aerosolized of pancreatic juice into airway could induce obstructive and restrictive ventilatory insufficiency which are related to the juice-induced lung inflammation by which increase of blood concentration of white cells in pulmonary capillary. Decrease of RBC counts and increase of the concentrations of hemoglobin, hematocrit, mean corporal volume, and the mean weight of hemoglobin. Besides, platelet concentration also decreased. These changes induced disseminated coagulation in the whole body. The increase of the concentrations of lactate dehydrogenase in the blood and in the lavage proved that juice-induced cells damage in the lung and whole body. The pulmonary function data demonstrated that maximum voluntary ventilation, maximum mid-expiratory rate, airway resistance, vital capacity, respiration work, peak expiratory flow rate, maximal mid-expiratory flow and forced expiratory flow 50% were all decreased. However, total lung capacity, residual volume and chord compliance increased. Those data showed that lung functions were all affected. After using curcumin, the data of protein in bronchoalveolar lavage fluid (BALF), oxidative stress, nitrosative stress, LDH in serum and the lung function parameters all showed protective effects by curcumin. Through this study we confirmed that curcumin has potent antioxidant capacity by which oxidative and nitrosative stresses are attenuated. In conclusion, curcumin exerted its protective effects on pulmonary functions. In addition, through this study we also established the experimental model by aerosolized of pancreatic juice to the lungs to induce lung injury. This provides a good model on inflammation of the pancreas and lung diseases.

目 錄
第一章 研究動機………………………………………….…….1
第一節 肺臟組織…………………………………………………....1
第二節 肺損傷……………………………………………...….…....1
第三節 胰臟炎、胰臟癌…………………………………………….3
第四節 薑黃素……………………………………………………....6
一、薑黃的發現及應用………………………………………………….6
二、薑黃素的命名………………………………………………………..7
三、薑黃素的運用………………………………………………………..7
第二章 文獻探討……………………………………..…………..9
第一節 肺損傷……………….……………………………………..9
一、COPD…………………………..…………………………………….9
二、肺纖維化…………………………………………………………....10
三、輻射與抗生素…………………………………..…………………..11
第二節 胰液………………………………………………………..12
一、絲胺酸蛋白酶……………………………………………………....13
二、天門冬胺酸蛋白酶……………………………………….…………14
三、基質金屬蛋白酶…………………………………………………....14
四、半胱胺酸蛋白酶…………………………………………………....16
第三節 自由基……………………………………....…………….17
一、超氧歧化酶(SOD)………………………………………………….17
二、NO…………………………………………………………………..18
三、機械通氣肺損傷…………………………………………………....19
第四節 缺血再灌流………………………………………………..20
一、氧化物……………….………………………………………………20
二、抗氧化………………………………………………………………21
三、缺血再灌流實驗……………………………………………………21
第五節 離體肺灌流…………………………………………….....23
第六節 呼吸機……………………………………...……………..24
第七節 抗氧化、抗發炎……………………….…………………25
第八節 薑黃素………………………………………………….....25
一、薑黃素的特性與屬性……………………………………………....25
二、薑黃素的相關研究…………………………………………….……27
三、薑黃素的抗發炎的作用…………………………………………....28
(一) 生長因子………………………………………………………29
(二) 轉錄因子………………………………………………………29
(三) 細胞激素………………………………………………………33
(四) 酵素……………………………………………………………34
(五) 細胞受體………………………………………………………35
(六) 抗發炎機制……………………………………………………36
四、薑黃素與抗氧化……………………………………………………..36
五、薑黃素與肺損傷、纖維化………………………………………….38
六、薑黃素與肺部疾病……………………………………………….....39
(一) COPD………………………………………………………......39
(二) 硬皮病…………………………………………………………40
(三) ARDS與ALI…………………………………..........................41
(四) 氧化壓力………………………………………………………42
七、薑黃素的療效…………………………………………………….....42
(一) 薑黃素與前列腺素………………………………………........43
(二) 薑黃素與氧自由基………………………...………………….43
(三) 抗發炎藥劑…………………………………………………...44
八、薑黃素運用於疾病上……………………………………………....46
(一) 發炎性疾病……………………………………………………46
(二) 中樞神經疾病…………………………………………………47
(三) 心臟疾病………………………………………………………47
(四) 慢性疾病………………………………………………………47
(五) 腫瘤……………………………………………………………48
九、薑黃素運用於肺部疾病……………………………….…………...51
第九節 二甲基硫脲(DMTU)……………………………………...52

第三章 研究材料與方法…………………………………........53
第一節 實驗規範及分組……………………………...…………..53
一、實驗動物人道管理…………………………………………………53
二、胰液之準備……………………….…………………………………53
三、薑黃素配置………………………………………………………....54
四、實驗動物準備……………………………………………...……….54
(一) 胰臟缺血再灌流(急性胰臟炎)……………………………….54
(二) 肺臟缺血再灌流(離體肺灌流)……………………………….54
(三) 直接噴灑胰液至呼吸道………………………........................55
第二節 血液檢體檢測…………………………………………….55
一、血液檢體製備………………………………………...…………….55
二、全血血球計數(CBC)…………………………………...…………..56
三、血漿中澱粉酶(amylase)活性…………………….…………………56
四、血清生化及免疫數值檢測………………………………………....56
(一) 抽取動脈血取血清………………………………….........…...56
(二) 檢測methyl guanidine………………………………..……….56
(三) 檢測白三烯素(leukotriene) ……………………………...…...56
(四) 檢測LDH……………………………………………………...56
(五) 檢測過氧化氫………………………………………………...57
(六) 檢測H2O2自由基產物………………………………………..57
(七) 檢測亞硝酸鹽/硝酸鹽(nitrite/nitrate) ………………………..57
(八) 檢測TNF-α……………………………………………………58
第三節 BALF檢測………………………………………….......…58
一、BALF檢體製備…………………………..………………………….58
二、BALF生化試驗及血球計數……..………………………………….58
三、BALF中methyl guanidine的測量…………………………………58
四、BALF白血球分類…………………………………………………...59
五、BALF白血球分類百分比…………………………………………...59
第四節 全體腔呼吸測量(WBP)……………………………….....59
第五節 全套肺功能相關生理試驗(PFT) ……………...…………60
一、肺功能相關的PFT數值收集……………………………………...60
二、Methacholine challenge支氣管反應能力…………………………61
三、非侵入性氣道偵測儀(NAM)……………………………………....61
四、PFT試驗…………………………………………………………....61
第六節 肺組織與檢體………………………………………….....63
一、肺組織與檢體的製備……………………………………………....63
二、肺臟濕乾比值(W/D) …………………………………………….....63
三、mRNA在iNOS的表現……………………………………………63
四、即時PCR (RT-PCR)測量………………………………………….63
五、測定iNOS蛋白在肺組織的表現量……………………………….64
第七節 數值分析……………………………………………….....64

第四章 結果…………………………….……………………….65
第一節 血液檢體檢測(直接噴灑胰液實驗)………….……….....65
一、全血血球計數(CBC)……………………………………………….65
(一) WBC的數量變化……………………………………………...65
(二) RBC的數量變化………………………………………………65
(三) 血紅素(hemoglobin, HGB)的濃度變化………………………65
(四) 血球容積比(hematocrit, Hct)的變化…………………………65
(五) 血小板數量的變化…………………………………………...65
(六) 紅血球容積(MCV)的變化……………………………………66
(七) 平均紅血球血紅素重量(MCH)的變化………………………66
(八) 平均紅血球血紅素濃度(MCHC)的變化………………..…...66
二、血漿檢體(胰臟缺血再灌流實驗)………………………………….66
三、血清檢體(直接噴灑胰液實驗)…………………………………….66
(一) NO的濃度變化…………………………...…………………....66
(二) Methylguanidine的濃度變化…………………….…………....67
(三) LDH濃度的變化………………………………………………67
第二節 肺部組織檢體………………………………………….....67
一、肺組織(直接噴灑胰液實驗)………………………………………...67
二、肺滲透係數(Kf, c)變化(肺臟缺血再灌流實驗)…………………....68
三、肺泡灌洗液(BALF)中白蛋白含量變化(肺臟缺血再灌流實驗).....68
四、肺重與體重比值(W/D)的變化(肺臟缺血再灌流實驗)……………68
五、肺臟濕乾比值(濕重/乾重) (直接噴灑胰液實驗)………………......68
六、肺組織灌洗液中白血球數量變化(直接噴灑胰液實驗)…………...69
七、肺組織灌洗液中巨噬細胞的比例變化(直接噴灑胰液實驗)……...69
八、肺組織灌洗液中leukotriene的濃度變化(直接噴灑胰液實驗)…..69
九、肺組織灌洗液中methylguanidine的濃度變化(直接噴灑胰液).....69
十、肺組織灌洗液中LDH的濃度變化(直接噴灑胰液實驗)….………70
第三節 肺功能測試………………………………………………..70
一、Penh實驗方式(胰臟缺血再灌流實驗)…………………………....70
二、全套肺功能相關生理試驗(PFT) (直接噴灑胰液實驗)…………..70
(一) 最大自發性換氣量(MV)的變化………………………….......70
(二) 中間潮氣呼氣流量(EF50)的變化……..………………….......70
(三) Resistance index (RI)的變化………………………………......71
(五) 功能肺餘容量(FRC)的變化……………….………..…….......71
(六) 肺總量(TLC)的變化……………….………………………….71
(七) 肺餘容積(RV)的變化……………….…………………….......71
(八) Chord compliance (Cchord)的變化……………….…………...72
(九) 呼吸功(work)的變化……………….………………………....72
(十) 最大呼氣流速(PEF)的變化….……………………………….72
(十一) 最大中段吐氣流量(MMEF)的變化….…………………….72
(十二) 用力吐氣時間在50%的氣體流量(FEF50)變化….………..73

第五章 討論…………………………………………………….74
第一節 抑制細胞作用…………..………………………………..74
一、通透性…………………………………………………………...….74
二、白血球……………………………………………………………....75
三、紅血球……………………………………………………………....75
(一) 紅血球數量……………………………………………………75
(二) 血球容積比…………………………………………….….......76
(三) 平均紅血球容積………………………………..…………......76
(四) 平均紅血球血紅素重量………………………………..…......76
(五) 平均紅血球血紅素濃度………………………………………77
(六) 血紅素…………………………………………………………77
四、血小板……………………………………………………………....77
第二節 抑制發炎酵素…………………………………...………77
一、LDH…………………………………………………………………78
二、SOD…………………………………………………………………79
第三節 抑制細胞訊息傳遞……………………………………….79
第四節 抑制發炎基因轉錄……………………………………….80
第五節 抑制發炎酵素與自由基………………………………….80
第六節 抑制氧化壓力與氮化壓力………………………………82
第七節 抗氧化與抗發炎…………………………………….…...82
第八節 全套肺功能相關生理試驗(PFT)………………………..83
一、最大自發性換氣量(MV)…………………………………………..83
二、中間潮氣呼氣流量(EF50)………………………………………....83
三、阻力指數(RI)…………………………………………………….....84
四、肺活量(VC)…………………………………………………………84
五、功能肺餘容量(FRC)……………………………………………….84
六、肺總量(TLC)……………………………………………………….84
七、肺餘容積(RV)………………………………………………………85
八、Chord compliance (Cchord)……………………………………….85
九、呼吸功(Work)…………..…………………………………...………85
十、最大呼氣流速(FEFmax)…………...………………………………86
十一、最大呼氣流速(PEF)………………..……………………………86
十二、最大中段吐氣流量(MMEF)…………….………………………86
十三、用力吐氣時間在50%的氣體流量(FEF50)………..…………..86
第九節 藥物療效………………………………………………….87
第十節 結論……………………………………………………….88

參考文獻……………………………………………………….…....93
一、中文文獻…………………………………………………………………...93
二、西文文獻…………………………………………………………………...93
三、網路資訊……………………………………………………………….....133

圖 表
表1.血漿中澱粉酶、氫氧自由基、NO、TNF-α和白血球(血漿與BALF)等，在sham組、I/R組及curcumin組中的參數值…………………………………………136
表2. 在I/R誘導肺損傷前後的肺滲透係數、肺部組織支氣管灌洗液白蛋白的含量與肺I/R損傷後肺重與體重比值(LW/BW)的變化……………………………137
圖1. 血液常規檢測CBC中白血球(WBC)的數量變化………………..…………..138
圖2. 血液常規檢測CBC中紅血球(RBC)的數量變化…….……………...…….....139
圖3. 血液常規檢測CBC中血紅素(HGB)的濃度變化……...…………………......140
圖4. 血液常規檢測CBC中血球容積比(Hct)的變化………………….....…………141
圖5. 血液常規檢測CBC中血小板數(pletelet)量的變化………………...…………142
圖6. 血液常規檢測CBC中平均紅血球容積(MCV)的變化………………..……...143
圖7. 血液常規檢測CBC中平均紅血球血紅素重量(MCH)的變化………..……...144
圖8. 血液常規檢測CBC中平均紅血球血紅素濃度(MCHC)的變化………...…...145
圖9. 血清中NO的濃度變化………………………………………..………..……..146
圖10. 血清中羥自由基methylguanidine (MG)的濃度變化………………...………147
圖11. 血清中LDH濃度的變化…………………………………………………......148
圖12.誘導型一氧化氮合酶和腫瘤壞死因數-α的mRNA在sham組、I/R和使用curcumin預先處理組的表現……………………………………………...…….149
圖13. 肺臟組織重量的乾溼比的變化……………………….………………….......150
圖14. 肺組織灌洗液中白血球(WBC)數量變化……………….……………..…….151
圖15. 肺組織灌洗液中巨噬細胞(by Liu's stain )的比例變化………………….......152
圖16. 肺組織灌洗液中白三烯素(leukotriene)的濃度變化…………………….......153
圖17. 肺組織灌洗液中methylguanidine (MG)的濃度變化.……………………….154
圖18. 肺組織灌洗液中LDH的濃度變化.………………………………………….155
圖19. Penh實驗方式，在sham組、I/R組和curcumin預先處理組的變化…...…..156
圖20. 肺功能試驗(PFT)中最大自發性換氣量(MV)的變化………………..……...157
圖21. 肺功能試驗(PFT)之中間潮氣呼氣流量(EF50)的變化……………..……….158
圖22. 肺功能試驗(PFT)中阻力指數(RI)的變化……………………...…………….159
圖23. 肺功能試驗(PFT)中肺活量(VC)的變化…………………………………......160
圖24. 肺功能試驗(PFT)中功能肺餘容量(FRC)的變化……………………………161
圖25. 肺功能試驗(PFT)中肺總量(TLC)的變化…………………………………....162
圖26. 肺功能試驗(PFT)中肺餘容積(RV)的變化………………………………......163
圖27. 肺功能試驗(PFT)中chord compliance (Cchord)的變化…………………….164
圖28. 肺功能試驗(PFT)中呼吸功(work)的變化……………………………………165
圖29. 肺功能試驗(PFT)中最大呼氣流速(PEF)的變化………...…………………..166
圖30. 肺功能試驗(PFT)中最大中段吐氣流量(MMEF)的變化…………...……….167
圖31. 肺功能試驗(PFT)中用力吐氣時間在50%的氣體流量(FEF50)變化……….168

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