臺灣博碩士論文加值系統

Cyclophosphamide是一種二氯甲基二乙酸(mechlorethamine)的衍生化合物，屬於alkylating類的抗腫瘤藥物。Acrolein是這類藥物經由肝臟酵素P450(cytochrome P450)而產生的尿液代謝產物。在兒童血液腫瘤疾病的治療上，它可能會直接造成膀胱傷害而引起常見的出血性膀胱炎併發症。它的發生率可以從7%到75%，其中可能會造成血尿、頻尿、排尿疼痛、甚至膀胱大量出血的症狀而導致死亡。動物模式中，將Acrolein注射入膀胱或cyclophosphamide直接注射入腹腔造成出血性膀胱炎，模擬化療藥物治療後的副作用。文獻指出，一氧化氮合酶(nitric oxide synthase, NOS)和氧化壓力一直為發炎反應重要機轉。在大鼠泌尿道感染所造成的平滑肌收縮力,NOS亦直接參與。對於化療藥物造成的出血性膀胱炎也是扮演很重要的病理機轉角色。然而，對於化療藥物cyclophosphamide所引起的出血性膀胱炎，NOS、氧化壓力與細胞訊息傳導的相互關係以及是否影響膀胱排尿肌的收縮並沒有清楚的瞭解。同時，目前也沒有有效的檢查方式來早期預測出血性膀胱炎的發生。8-iso-prostaglandin F2α為已知的脂肪受損的產物，這產物可以當作是氧化侵襲的生物指標。尿氮化合物(NOx)為NO代謝後在尿液出現的穩定產物，也可以代表體內NO生成的情形。過去文獻指出8-iso-prostaglandin F2α的代謝物在成人及小兒氣喘、慢性阻塞性肺疾病、間質性肺病、急性心、肺、腎臟的傷害和膽汁淤積性肝炎等的病人血液、尿液中，皆可以見到上升的情形。然而，對於化療藥物所引起的出血性膀胱炎，卻較少這方面的探討。因此，本研究將去探討cyclophosphamide造成膀胱傷害中，NOS、氧化壓力與細胞訊息傳遞因子的交互關係。同時，也希望藉由收集病童尿液中的NOx、8-iso-prostaglandin F2α來評估化療藥物對於出血性膀胱炎的影響。
研究結果顯示在動物模式中，使用cyclophosphamide的代謝產物acrolein (75 μg)，利用微小導尿管注入幼鼠膀胱內造成出血性膀胱炎，在24小時後可以明顯發現膀胱出血同時有iNOS顯著增加的情形。蛋白質致活酶(PKC)會在早期1、6小時上升，並且伴隨著膀胱肌肉的張力上升，但是在24小時後，隨著iNOS增加而抑制PKC的表現也同時抑制膀胱肌肉的張力。另一方面，在幼鼠的尿液收集中也發現尿氮化合物(NOx)及IL-6的上升。因此使用iNOS抑制劑或者使用IL-6的抗體皆會減少iNOS的產生，同時恢復原本下降的膀胱肌肉張力。代表在IL-6在調控NO/iNOS及PKC訊息傳導的幼鼠出血性膀胱炎及肌肉的張力改變上，扮演一個重要角色。進一步我們也利用直接腹腔注入cyclophosphamide的小鼠動物模式，發現iNOS及尿液中的NOx也是增加的情形，同時我們注入尿酸，它本身也是一種抗氧化物質，發現與iNOS抑制劑有著相同減緩出血性膀胱炎及回復PKC的作用。同時，我們回顧過去10年來因為化療藥物cyclophosphamide而導致出血性膀胱炎的病童，發現其血液中尿酸值的改變似乎影響出血性膀胱炎的程度。配合臨床上收集使用cyclophosphamide治療的病童尿液，也證實NOx及氧化壓力指標8-iso-prostaglandin F2α會有明顯上升的情形。綜合上述，尿酸對於出血性膀胱炎也許有些保護的角色；也證實氧化壓力及NOS的確佔有一定的角色。從臨床的觀察及後續的動物實驗中，希望能夠找到更好的方式來減少因為化療藥物所造成的兒童出血性膀胱炎。

口試委員審定書 ………………………………………………….I
誌謝 ………………………………………………………………. II
中文摘要 …………………………………………………………. III
Abstract …………………………………………………………… V
List of Abbreviation ………………………………………………VII
I. Introduction …………………………………………………….. 1
1.1 Nitric Oxide Synthase Related Signals and Disorder 1
1.2 Chemotherapy-Induced Bladder Injury and Nitric Oxide Synthase ………………………………………………………. 4
1.2.1 Cyclophosphamide-induced bladder injury………………………... 4
1.2.2 Acrolein, a urinary metabolite of cyclophosphamide, induced hemorrhagic cystitis…………………………………………………. 6
1.2.3 The roles of interleukin-6, uric acid, and nitric oxide synthase in bladder injury………………………………………………......… 7
1.3 The Aims of This Study…………………………………..…… 8
II. Materials and Methods……………………………………...…13
2.1 Clinical cyclophosphamide-induced bladder injury...…....… 13
2.1.1 Children with hemorrhagic cystitis……………………………….…. 13
2.1.2 Children with cyclophosphamide treatment…………………….….. 13
2.1.3 Measurement of nitrite/nitrate (NOx) levels…………………………14
2.1.4 Bladder oxidative injury assessment: 8-isoprostane assay…………. 14
2.2 Animal study in bladder injury……………………....…....… 15
2.2.1 Cyclophosphamide-induced hemorrhagic cystitis in mice………… 15
2.2.2 Western blot analysis…………………………………………….…… 15
2.2.3 Measurement of nitrite/nitrate (NOx) levels……………………….... 16
2.2.4 Histopathology and Immunohistochemistry……………………..….. 16
2.2.5 Acrolein-triggered hemorrhagic cystitis in rats……………….……... 17
2.2.6 Preparation of bladder detrusor strips…………………..………….. 18
2.2.7 Measurement of IL-6 and nitrite/nitrate (NOx) levels……………... 18
2.2.8 Western blotting in bladder………………………………………….. 19
2.2.9 Histological and immunohistochemistrical assessment…………..... 20
2.2.10 Statistical analysis…………………………..……………..……….… 20
III. Results…………………………………………………..…....… 21
3.1 Cyclophosphamide-induced hemorrhagic cystitis and
clinical implication………………………………….…..………21
3.1.1 Demographic data in children with hemorrhagic cystitis.….….….… 21
3.1.2 Urine NOx levels in children with cyclophosphamide chemotherapy. 22
3.1.3 Protein expressions of iNOS in mouse urinary bladders………...….. 22
3.1.4 The roles of uric acid and urine NOx levels……...……...……...….... 23
3.1.5 Histological and immunohistochemical changes in bladders……...... 23
3.2 Acrolein-triggered hemorrhagic cystitis..……………………. 23
3.2.1 Hemorrhagic cystitis and protein expressions in rat………………...23
3.2.2 Protein expressions of iNOS and phosphorylated PKC in rat………24
3.2.3 Urine IL-6 and NO levels after intravesical instillation of acrolein… 24
3.2.4 IL-6 and NO in altered contractile responses in bladders………...… 24
3.2.5 Histological and immunohistochemical changes in rat bladders….... 25
IV. Discussion ………………………27
4.1 The NOS and ROS involves in the cyclophosphamide-induced hemorrhagic cystitis………………27
4.2 The role of IL-6 and NOS in acrolein-triggered hemorrhagic cystitis…………………………. 30
V. Summary and Perspective ………………………………………34
Reference ……………………………………………………...……. 36
Appendix ……………………………………………….….……...... 82
1. List of Publication: …………………………………….……..…...… 82
2. Permission of Clinical Trial ………………………………….……..…83

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