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系統識別號 U0026-1901201212463100
論文名稱(中文) 燒傷水疱溶液在傷口癒合的血管新生時期所扮演的角色
論文名稱(英文) The role of burn blister fluid in burn wound neovascularization
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 1
出版年 101
研究生(中文) 潘信誠
研究生(英文) Shin-Chen Pan
學號 s9891108
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-邱浩遠
指導教授-吳梨華
召集委員-黃玲惠
口試委員-蔡美玲
口試委員-林幸道
口試委員-陳理維
中文關鍵字 灼傷水疱溶液  傷口癒合  血管新生  脈管形成  血管生成素 
英文關鍵字 Burn blister fluids  Wound healing  Angiogenesis  Vasculogenesis  Angiogenin 
學科別分類
中文摘要 傷口癒合是一個非常複雜的過程,包含了各種細胞及化學物質之間的相互作用。這個過程可分為發炎期,增生期及重新塑造期。新血管形成是傷口癒合必經的過程,從發炎期開始,即有這個現象發生。它包含了血管新生及脈管形成這兩個過程。
一般而言,淺二度灼傷傷口在兩週內即可癒合,且不會有疤痕產生,而深二度灼傷傷口通常需兩週以上的時間才會痊癒,而且容易產生難看的疤痕。通常都需要積極的治療,以避免疤痕產生。燒傷水疱溶液在以上兩種傷口皆會產生。臨床上,水疱會阻礙醫師對於傷口的觀察,以前的研究顯示,水疱溶液內含有多種細胞激素,這些因子會促進表皮細胞的增生。然而,水疱溶液對新血管形成的作用並不清楚。肥厚性疤痕本身是一個富含血管的組織,因為深二度灼傷傷口容易產生疤痕,合理推論這類傷口的新血管形成是比較豐富的,參與新血管形成的因子亦可能出現在早期水疱形成的過程中。
經由這樣的假設,我們藉由抽取兩種不同傷口病人身上的水疱溶液,測試它們在新血管形成的過程是否有異。經由體外及體內實驗顯示深二度水疱溶液較淺二度水疱溶液更容易有新血管的形成。
對於這樣的結果,我們深感興趣。希望能找出影響這個結果的關鍵因子。我們利用抗體陣列晶片及酵素免疫分析法發現血管生成素這個因子在兩種不同溶液中有明顯不同的表現量。我們繼續利用體外,動物及人體傷口組織實驗,證實此一因子在燒傷傷口癒合的新血管形成時期,佔有重要的地位。
在燒傷初期,快速並正確的判斷傷口的深度並積極的治療,是決定傷口預後的重要因素。然而,即便是有經驗的醫師,亦無法從完整的水疱上正確判斷傷口的深度。雖然我們發現血管生成素在深二度及淺二度水疱溶液內有顯著不同,臨床上應用此一因子來檢測傷口的深度仍需進一步的研究。但是,利用水疱內容物來觀察傷口癒合中細胞與週圍環境的相互作用,是研究傷口癒合過程中一有趣的話題。
英文摘要 Burn wound healing is a complex and dynamic process, which involves an interaction between different cells and mediators. This process can be divided into inflammatory phase, proliferative phase, and remodeling phase. Neovascularization, beginning during the inflammatory phase of wound healing, is an imperative stage of wound healing. The whole process consists of not only angiogenesis but also adult vasculogenesis.
Superficial partial thickness burn (SPTB) heals within 2 weeks without scarring. Deep partial thickness burn (DPTB), on the other hand, heals beyond 2 weeks and requires aggressive treatment to prevent hypertrophic scarring. Burn blisters on the skin are a hallmark of not only SPTB but also DPTB. Previous study reported that blisters contained several cytokines with beneficial effects on keratinocyte proliferation. However, the effect of burn blister fluids on the neovascularization has not been fully explored. Burn hypertrophy scar usually exhibits in a hypervascular status. DPTB wounds often result in hypertrophy scar, we assume that the neovascularization between SPTB and DPTB wounds may be different.
To verify this hypothesis, neovasculogenic effect of two different kinds of burn blister fluids was tested and compared in vitro and in vivo. The results show DPTB blister fluids more predominantly support neovascularization than do SPTB wounds in the early stage of wound healing.
Following the above study, we are particularly interested in investigating the factors modulating the differential angiogenic activity of these fluids. An expression analysis of angiogenic factors in burn fluids was conducted. Upon finding a significant difference of angiogenin between the two different burn fluids, the role of angiogenin was assessed in vitro, in vivo and human study. We find that angiogenin clearly involves in the neovascularization of burn wound healing.
Rapid and accurate assessment of burn depth is the most important determinant of burn wound management in the early stage of burn injury. However, assessment of second-degree burn wounds with intact blisters has always been difficult, even for experienced surgeons. Although our finding demonstrates a significantly higher angiogenin expression in DPTB blister fluids than formed in SPTB fluids, screening the angiogenin in burn blister fluids for determination of burn depth should be further studied. Nevertheless, application of burn fluid contents to observe cell-mediators interaction in burn wounds is of considerable interest to those investigating the processes of burn wound healing.
論文目次 CONTENT LIST PAGE

Chinese abstract 3
English abstract 5
Acknowledgements 7
Abbreviations 13
Chapter 1 Burn Blister in Burn Wound Healing
1.1 Phases of Normal Wound Healing 15
1.1.1 Inflammation phase 15
1.1.2 Proliferative phase 16
1.1.2.1 Angiogenesis 17
1.1.2.2 Vasculogenesis 18
1.1.2.2.1 Characterization of circulating EPC 19
1.1.2.2.2 Role of EPCs in Neovascularization 20
1.1.2.2.3 Mechanisms by which EPCs promote 21
neovascularization
1.1.2.2.4 Mobilization of EPCs 22
1.1.2.2.5 Chemotaxis of EPCs 22
1.1.2.2.6 Homing and differentiation of EPCs 23
1.1.2.2.7 Vasculogenesis in wound healing 24
1.1.3 Remodeling phase 26
1.2 The Burn Wound 27
1.2.1 Anatomy of normal skin 27
1.2.2 Thermal effect on skin 28
1.2.3 Depth of the Burn 29
1.2.4 First-degree burn 29
1.2.5 Second-degree burn 29
1.2.6 Third-degree burn 30
1.2.7 Fourth-degree burn 30
1.2.8 Assessment of burn wound depth 30
1.2.8.1 Clinical evaluation 31
1.2.8.2 Biopsy and histology 32
1.2.8.3 Thermography 33
1.2.8.4 Vital dyes 34
1.2.8.5 Indocyanine green video angiography 35
1.2.8.6 Laser Doppler flowmetry 35
1.2.8.7 Nuclear imaging 37
1.2.8.8 Noncontact and high-frequency 38
ultrasound
1.3 Burn blister 39
1.3.1 Occurrence of blister 39
1.3.2 Advantages of blisters intact 40
1.3.3 Advantages of blister removal 41
1.4 Conclusion 43
1.5 Goal of Ph.D project 44
Chapter 2 The Effect of Superficial And Deep Partial Thickness Burn Blister Fluid in Burn Wound Neovascularization
2.1 Introduction 46
2.2 Materials and Methods 46
2.2.1. Patient samples 46
2.2.2 Immunohistochemistry 47
2.2.3 Cell proliferation assay 48
2.2.4 Isolation and differentiation of circulating 48
angiogenic cells
2.2.5 Isolation of CD34+ and CD14+ cells 49
2.2.6 Transwell migration assay 49
2.2.7 Real-time polymerase chain reaction (PCR) 50
2.2.8 Characterization of endothelial cells 50
2.2.9 Matrigel plug assay 51
2.2.10 Statistical analysis 51
2.3 Results 51
2.3.1 Microvascular density in different burn 51
wounds
2.3.2 Proliferative ability of endothelial cells in 52
burn blister fluids
2.3.3 Migration ability of CACs in burn blister 52
fluid
2.3.4 Endothelial gene expression in burn blister 52
fluids
2.3.5 Production of functional endothelial cells in 53
burn blister fluids
2.3.6 In-vivo animal study of burn blister fluids 54
2.3.7 Purity of CD34+ and CD14+ cells 54
2.3.8 Migration ability of CD34+ and CD14+ cells 54
in burn blister fluids
2.3.9 The endothelial gene expression of CD34+ 55
and CD14+ cells in burn blister fluids
2.3.10 Endothelial characteristics of CD34+ and 55
CD14+ cells in burn blister fluids
2.4 Discussion 55
2.5 Conclusion 58
Chapter 3 Factors modulating the angiogenic activity of burn blister fluids
3.1 Introduction 60
3.2 Materials and Methods 60
3.2.1. Patient samples 60
3.2.2 Cytokine antibody assay 61
3.2.3 Enzyme-linked immunosorbent assay (ELISA) 61
3.2.4 Cell proliferation assay 62
3.2.5 CAC isolation and differentiation 62
3.2.6 Endothelial cell characterization 62
3.2.7 Matrigel plug assay 63
3.2.8 Immunohistochemistry 63
3.2.9 Statistical analysis 64
3.3 Results 64
3.3.1 Differential angiogenesis-related cytokine 64
expression in burn blister fluids
3.3.2 Effect of endothelial cell proliferation by 65
angiogenin neutralization
3.3.3 Correlation of angiogenin expression with 66
CAC differentiation
3.3.4 CACs differentiation by angiogenin inhibition 66
3.3.5 Angiogenin neutralization attenuated 67
neovascularization in vivo
3.3.6 Angiogenin expression in human burn wound 67
tissues
3.4 Discussion 68
3.5 Conclusion 72
Chapter 4 Conclusion 73
Chapter 5 Future Work 75
Reference List 76
Tables 95
Figures 98
List of thesis related publications 122
Curriculum Vitae 123
Grants 124
Publications 125

LIST of TABLES
Table 1 The number of CAC differentiation in patients 95
according to burn severity
Table 2 ELISA analysis of cytokines in blister fluids 96
Table 3 Angiogenin staining intensity in human burn 97
wound tissues
LIST of FIGURES
Figure 1. Common methods of “EPC” culture 98
Figure 2. Origin and differentiation of endothelial 99
progenitor cells
Figure 3. Immunohistochemical staining of CD31 in 100
SPTB and DPTB wounds
Figure 4. The effect of burn fluids on endothelial 101
cell proliferation
Figure 5. The migration ability of peripheral blood 102
mononuclear cells induced by SPTB or DPTB
blister fluids
Figure 6. The effect of burn blister fluids on the 103
endothelial mRNA expression
Figure 7A. The effects of burn blister fluids on CACs 104
differentiation
Figure 7B. Flow cytometry analysis of endothelial 105
differentiation of CACs
Figure 8. In vivo angiogenic activity of burn 106
blister fluids
Figure 9. Purity of CD34+ and CD14+ cells 107
Figure 10. Migration ability of CD34+ and CD14+ 108
cells in DPTB blister fluid
Figure 11. The vWF mRNA gene expression of cultured 109
CD34+ and CD14+ cells in DPTB blister
fluids
Figure 12A.Flow cytometry analysis of CACs 110
differentiation from cultured CD34+,
CD34-, CD14+ and CD14- cells.
Figure 12B.Differentiation of cultured CD34+ and 111
CD14+ cells in DPTB blister fluids
Figure 13. Differential expression of cytokines in 112
SPTB and DPTB fluids
Figure 14. Time course of cytokines expression in 113
burn blister fluid following thermal
injury
Figure 15. The effect of anti-angiogenin antibodies 114
on endothelial cell proliferation
Figure 16. The effect of different levels of 115
anti-angiogenin antibody on endothelial
cell proliferation
Figure 17. The effect of angiogenin on CAC 116
differentiation
Figure 18. The effect of neutralizing antibody to 117
angiogenin on CAC differentiation induced
by DPTB fluid
Figure 19. The effect of VEGF-A neutralization on 118
DPTB fluid-induced CAC differentiation
Figure 20. Angiogenin neutralization in DPTB fluids 119
reduced neovascularization in Matrigel plugs
Figure 21. The relationship between angiogenin and 120
neovascularization in human burn wounds
Figure 22. Summary of differential neovascularization 121
between superficial and deep partial
burn wounds
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