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系統識別號 U0026-2510201810440900
論文名稱(中文) 在規律機械力下腕隧道症候群中次滑膜結締組織的發炎激素調控機制
論文名稱(英文) The regulatory mechanism of inflammatory cytokines in subsynovial connective tissue(SSCT) of carpal tunnel syndrome(CTS)
校院名稱 成功大學
系所名稱(中) 生物醫學工程學系
系所名稱(英) Department of BioMedical Engineering
學年度 106
學期 2
出版年 107
研究生(中文) 張澤文
研究生(英文) Tse-wen Chang
電子信箱 je2230507@gmail.com
學號 P86054234
學位類別 碩士
語文別 英文
論文頁數 137頁
口試委員 指導教授-楊岱樺
共同指導教授-蘇芳慶
口試委員-許太乙
口試委員-吳炳慶
口試委員-楊曉白
中文關鍵字 腕管綜合症  發炎  滑膜下結締組織  類固醇治療 
英文關鍵字 carpal tunnel syndrome  inflammation  subsynovial connective tissue  steroid treatment 
學科別分類
中文摘要 簡介:腕管綜合徵(CTS)是世界常見的疾病之一,CTS是由於SSCT壓迫正中神經所產生的疾病,現行常用的治療方法為末期的手術治療與初中期使用類固醇注射治療,類固醇是常見治療發炎的有效藥劑,但是目前的研究指出於末期CTS的患者檢體並沒有發炎的證據被顯示,然而卻有組織纖維化與TGF-β上調的等傷口癒合機制的證據出現,因此本研究企圖通過體外細胞模型與體內動物實驗交互驗證,驗證CTS的前期進程中是否有發炎反應參與其中,以致類固醇治療可有效降低CTS患者的症狀。
材料和方法:本實驗通過建立體內和體外模型模仿CTS的症狀。於體外細胞模型中,NIH3T3在於規律的重複拉伸下通過控制時間與拉伸頻率等變因來模擬CTS病患過度使用手部的情況,然後使用西方墨點法、細胞因子陣列確認模型中炎症相關細胞因子的變化,再對體外模型使用類固醇與DMSO進行治療比對。體內模型是在動物腕部植入實驗用微量抽吸管以模擬SSCT壓迫正中神經,產生CTS症狀,動物實驗於第8週時施以類固醇與生理食鹽水進行治療比對,然後分別取樣,並於12及16週以壓力檢測器檢測壓力是否於實驗組上升,已確認實驗組產生CTS,再均使用免疫組織及H&E染色於動物腕部組織觀察其發炎反應和類固醇治療的效果。同時以MTS測試肌腱硬度,以比較CTS動物模型之控制組、實驗組中類固醇治療前後及不同時間對肌腱力學的影響。
結果: 在細胞模型中,炎症相關細胞因子,包括TGF-β、IL1-β、TNF-α、CXCL12,CXCR4在CTS早期階段均在0.5和2.0Hz上調。此外,膠原相關蛋白MMP9和TIMP1於結果中顯示與TGF-β的表現量高度相關。於類固醇治療的實驗中,我們檢查了炎症相關的細胞因子和膠原相關蛋白,它們的蛋白表現在類固醇治療的組別中階顯示有下調的情況。在動物模型中,TGF-β和CXCL12在CTS的早期階段被發現有上調的情況。 隨著時間的推移,TGF-β逐漸增加,但CXCL12卻隨之下調。此外,結果顯示於同一時間下,通過類固醇治療可以有效抑制TGF-β和CXCL12的上調。在MTS的實驗中,隨著時間的推移,CTS組別的FDS肌腱硬度呈現出增加的趨勢。 然而,FDS肌腱的硬度在類固醇治療後逐漸減少並接近於正常值。除此之外,我們以one way-ANOVA分析發炎相關細胞因子的半定量參數與傷口癒合機制以及類固醇治療與炎症的療效,相互間倆倆存在顯著相關性。肌腱的力學性質在控制組和實驗組中,以及治療控制組和類固醇組之間也存在顯著差異。
結論:基於上述實驗結果,我們證實CTS的前期確實有炎症反應的參與。類固醇可以有效治療模型中的發炎反應,並與實際治療結果一致,本研究可能成為未來藥物治療初中期CTS的基礎。
英文摘要 Introduction: Carpal tunnel syndrome(CTS) is one of the common diseases in worldwide. The general treatment is steroid injection in the early stage and surgery in the later stage. Steroids are usually used for treatment of inflammation, but there were no evidences of inflammation to be found. Therefore, the goals in this study was to validate whether there is the inflammation in the early stages of CTS, so that steroid treatment can effectively reduce the symptoms of CTS.
Materials and Methods: Cell and animal model were established to mimic the symptoms of CTS. NIH3T3 was cultured under the repeated loading force. Western blotting and cytokine arrays were used to understand changes of inflammation-related cytokines and steroid treatment in CTS model. In the animal model, an experimental tube was implanted in the carpal tunnel to mimic the symptoms of CTS. After 8 weeks, steroids and normal saline were applied in the treatment of CTS, and samples were taken at 8, 12 and 16 weeks. The pressure in the intra-carpal tunnel was measured, and IHC as well as H&E staining were used to observe the effects of inflammation and steroid treatment. Besides, MTS test was used to observe the change of mechanical properties in animal model.
Results: Results showed increased pressure of the intra-carpal tunnel in the animal model and the up-regulation of TGF-β in cell models were confirmed to be effective models of CTS. In the cell models, the inflammation-related cytokines, including TGF-β, IL1-β, TNF-α, CXCL12, CXCR4 were up-regulated at both of 0.5 and 2.0 Hz in the early stages of CTS. Besides, the collagen-associated proteins, MMP9 and TIMP1 were also examined there were high related with TGF-β. In addition, the inflammation-related cytokines and the collagen-associated proteins were examined they were down-regulated in the steroid treatment. In animal models, TGF-β and CXCL12 were up-regulated in the early stage of CTS. With time passed, TGF-β was increased gradually, but CXCL12 was decreased. In addition, TGF-β and CXCL12 were inhibited by steroid treatment. The stiffness of FDS tendons showed the increasing trends with time passed in the CTS groups. However, the stiffness of FDS tendons were decreasing gradually after steroid treatment.
Conclusion: One-way ANOVA was used for statistical analysis. There were significant correlations between the semi-quantative parameters of inflammatory cytokines and wound healing mechanism. Besides, in the comparison with control and steroid treatment group, the values of inflammatory cytokines were significantly decreased in steroid treatment group. The inflammation was validated it was participated in the early stage of CTS. The steroid treatment inhibited effectively the inflammation in CTS models.
論文目次 摘要 I
Abstracts II
Acknowledge III
List of Table VII
List of Figure VIII
Abbreviations XI
Chapter 1 INTRODUCTION 1
1.1 The prevalence of carpal tunnel syndrome 1
1.2 The anatomy of carpal tunnel 2
1.3 The pathogenesis of carpal tunnel syndrome 3
1.4 The etiology of carpal tunnel syndrome 4
1.5 Clinical presentation and diagnosis 4
1.6 Treatment of CTS 5
1.7 Wound healing 6
1.7.1 Early stage 7
1.7.2 Cellular stage 7
1.7.2.1 Macrophages 7
1.7.2.2 Fibroblasts 8
1.7.3 The wound healing of carpal tunnel syndrome 9
1.8 The markers of inflammation in CTS 9
1.8.1 TGF-β 9
1.8.2 IL1-β and TNF-α 10
1.8.3 CXCL12 and CXCR4 11
1.9 In-vitro and in-vivo model 12
1.9.1 In-vitro model 12
1.9.2 In-vivo model 13
1.10 Specific aims 14
1.11 Hypothesis 15
Chapter 2 MATERIALS and METHODS 16
2.1 Materials 16
2.1.1 NIH-3T3 and cell preparation 16
2.1.2 Sprague Dawley (SD) rats 17
2.2 Methods 17
2.2.1 The conditioned medium preparation 17
2.2.2 The in-vitro model under repeated loading force 18
2.2.2.1 The effect of time dependent 18
2.2.2.2 The effect of frequency dependent 18
2.2.3 Animal model 19
2.2.3.1 Creating animal model 19
2.2.3.2 The pressure measurement of carpal tunnel 19
2.2.3.3 Euthanasia and the processing of tissues 19
2.2.4 Western blotting 20
2.2.4.1 The gel making 21
2.2.4.2 Running and transferring the gel 21
2.2.4.3 Blocking and antibody staining 22
2.2.4.4 ECL-enhanced chemiluminescence system 22
2.2.5 Cytokine arrays 23
2.2.6 IF (Immunofluorescence) 24
2.2.7 Cytotoxicity assay 25
2.2.7.1 MTT assay 25
2.2.8 Steroid treatment 26
2.2.8.1 In-vitro model 26
2.2.8.1.1 The effect of DMSO in-vivo model 26
2.2.8.1.2 The effect of steroid in-vivo model 27
2.2.8.2 In-vivo model 27
2.2.9 MTS test 28
2.2.10 Formalin‐fixed paraffin embedded tissue 28
2.2.11 Histochemistry stain (H&E staining) 29
2.2.12 Immunohistochemistry (IHC) 30
2.2.13 Statistical analysis 31
Chapter 3 RESULTS 33
3.1 Establishment of CTS model in-vitro 33
3.1.1 The effect of time dependent in-vitro 33
3.1.2 The effect of frequency dependent in-vitro 39
3.2 Establishment of CTS model in-vivo 44
3.3 The effect of dexamethasone treatment in-vitro 46
3.4 The effect of dexamethasone treatment in-vivo 52
3.5 The mechanical property of tendons in-vivo 54
Chapter 4 DISCUSSION 57
4.1 Limitation 63
Chapter 5 CONCLUSION 64
Figure List 65
Table List 97
REFERENCES 107
SUPPLEMENTS 123
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