臺灣博碩士論文加值系統

間質性膀胱炎是一種慢性膀胱疾病，典型的表現包括膀胱漲痛、嚴重頻尿、急尿、夜尿多及恥骨上膀胱區脹痛。其真正致病原因至今還未清楚，部分專家認為是由許多不同原因所造成的，其中包括膀胱醣胺聚醣層損傷、肥大細胞活化及自體免疫疾病所引起的上皮功能障礙都可能為致病機轉。即便目前針對間質性膀胱炎有許多的治療方法，但卻尚未有長期且穩定的療效報告，因此提出新的治療策略對於間質性膀胱炎的治療具有迫切的需求。增生療法是一種用於肌腱韌帶關節損傷的常見療法，一般是使用高濃度葡萄糖溶液，以多點注射在受傷的肌腱韌帶上。目的是促使組織產生輕微的發炎，誘發玻尿酸增生反應，使其再次啟動修復機制，促進組織復原、減少疼痛。因此，我們認為葡萄糖治療可能是間質性膀胱炎治療的一種新策略。本研究目的是通過高濃度葡萄糖溶液，來修復受損的膀胱醣胺聚醣層以降低黏膜層下神經的衝動所引起的膀胱疼痛。首先我們建立以環磷醯胺誘導間質性膀胱炎之動物模型，用於評估膀胱灌注治療葡萄糖是否可以改善膀胱損傷、內生性玻尿酸的再生及尿路上皮的的修復。我們通過多種方法學包蘇木精伊紅染色、免疫組織化學和螢光染色、膀胱與體重測量法、機械疼痛測量、膀胱壓檢測及尿漬紀錄和即時聚合酶連鎖反應來驗證高濃度葡萄糖灌注的效用。實驗以大鼠每公斤七十五毫克的劑量進行腹腔注射環磷醯胺，每三天注射一次並連續注射三次，以建立間質性膀胱炎動物模式，而後於第七天進行葡萄糖膀胱灌注治療，第十四天犧牲動物進行檢體採樣。我們的結果顯示在膀胱灌注高濃度葡萄糖進行增生療法，有助於改善環磷醯胺誘導間質性膀胱炎大白鼠的機械性疼痛和降低頻繁排尿而在動物膀胱重量雖然沒有和間質性膀胱炎組有顯著差異，但在組織染色的結果發現葡萄糖灌注治療有助於改善基底膜細胞排列鬆散和尿路上皮增厚，促使膀胱表層細胞上醣胺聚醣層的再生和玻尿酸受體的表現，而在細胞外基質相關基因表現則發現葡萄糖灌注治療有助於玻尿酸受體和玻尿酸合成酶的增加。綜合上面的實驗結果，我們發現葡萄糖灌注治療可以提高疼痛閾值，增加膀胱黏膜層醣胺聚醣的再生和改善頻繁排尿，希未來能成為緩解膀胱疼痛和減輕間質性膀胱炎炎症的新策略。

Interstitial Cystitis / Bladder Pain Syndrome （IC/BPS） is a chronic bladder disease characterized by bladder pain while fullness, frequent urination, nocturia, urgency, and suprapubic pain. Although the pathogenesis of interstitial cystitis is unclear, it has been proposed that a dysfunctional epithelium, mast cell activation, and autoimmune disease may involve the etiology of IC/BPS. Many studies have established IC/BPS animal models to study pathological mechanisms and develop treatment strategies. Prolotherapy with dextrose has been used in treating chronic pain in neuromuscular and joint disorders widely, and it promotes cell proliferation and tissue remodeling of the injured tissue. Recently, a study has shown that dextrose injection adjacent to peripheral nerves may reduce neuropathic pain due to high dextrose-induced enrichment of endogenous hyaluronic acid （HA）. Thus, we propose that dextrose could be a novel strategy for IC/BPS treatment due to its potential to reduce peripheral sensitization in neuropathic pain, and neurogenic inflammation. In this study, we established cyclophosphamide （CYP）-induced interstitial cystitis rat model under the acute inflammation stage. Then we examined whether dextrose treatment can reduce inflammatory damage and increasing endogenous HA production, urothelium regeneration, or remodeling. The hematoxylin and eosin staining, immunohistochemical staining, weight （bladder/whole body） measurement, von frey filament （nociceptive pain）, cystometry, urination behavior test, and quantitative Polymerase Chain Reaction were used to explore the pathophysiology of IC/BPS, Our study showed that chronic cystitis was induced in rats by repetitive intraperitoneal injection of CYP. CYP（75mg/kg） was administered three times for six days. At 24 hours later, rats were treated with dextrose by single intravesical instillation. All animals were sacrificed one week after the third CYP injection was collected. Our research results show that intravesical administration of high concentration dextrose in the bladder for prolotherapy therapy could improve the CYP-induced mechanical allodynia and reduce the frequent urination in rats with IC/BPS. Although the results showed that there was no difference in the bladder weight of CYP-induced IC rats, the results of tissue staining showed that the dextrose treatment was helpful to improve the loose arrangement of basement membrane cells and thickened urothelium, promote the regeneration of the glycosaminoglycan layer on the bladder surface cells and the performance of hyaluronic acid receptors. In the expression of extracellular matrix-related genes, we found that dextrose treatment may help hyaluronic acid increase in the receptors and the hyaluronic acid synthesis. According to the above results, we found that dextrose treatment could improve the pain threshold, increase the regeneration of glycosaminoglycan in the bladder mucosa and improve frequent urination. It is hoped that it could become a new indication application for relieving bladder pain and reducing inflammation in IC/BPS.

目錄...I
圖目錄...III
表目錄...IV
中文摘要...V
英文摘要...VII
第一章、緒論...1
第一節、間質性膀胱炎...1
第二節、膀胱醣胺聚醣層...2
第三節、間質性膀胱炎治療策略...3
第四節、增生療法...5
第五節、葡萄糖增生療法...5
第六節、間質性膀胱炎動物模型...6
第七節、研究目的...7
第二章、材料與方法...8
第一節、實驗設計...8
第二節、動物實驗...8
壹、動物條件及來源...8
貳、間質性膀胱炎動物模型...9
參、葡萄糖灌注治療...10
肆、機械性疼痛測試...10
伍、尿漬紀錄...10
陸、活體尿路動力學測試...11
柒、蘇木精-伊紅染色...11
捌、艾爾遜藍染色...12
玖、過碘酸-席夫染色...12
拾、免疫組織螢光染色...13
壹拾壹、即時聚合酶連鎖反應...13
壹拾貳、統計分析...14
第三章、實驗結果...15
第一節、機械性疼痛...15
第二節、排尿及尿漬分析...16
第三節、組織學分析...17
第四節、胞外基質相關基因表達...19
第四章、討論...21
第五章、結論...26
第六章、圖...27
第七章、表...51
第八章、參考文獻...52

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